Novel multicyclic compounds and the use thereof

ABSTRACT

The present invention is directed to novel multicyclic molecules that mediate enzymatic activity. In particular, the compounds may be effective in the treatment of diseases or disease states related to the activity of PARP, VEGFR2, and MLK3 enzymes, including, for example, neurodegenerative diseases, inflammation, ischemia, and cancer.

FIELD OF THE INVENTION

[0001] The present invention relates to novel multicyclic compounds andthe use thereof More particularly, the present invention relates tonovel multicyclic compounds and their use, for example, for themediation of enzyme activity.

BACKGROUND OF THE INVENTION

[0002] Poly(ADP-ribose) polymerase (PARP, also called poly(ADP-ribose)synthetase, or PARS) is a nuclear enzyme which catalyzes the synthesisof poly(ADP-ribose) chains from NAD⁺ in response to single-stranded DNAbreaks as part of the DNA repair process (de Murcia et al. TrendsBiochem. Sci. 1994, 19,172; Alvarez-Gonzalez et al. Mol. Cell. Biochem.1994, 138, 33.). The chromatin-associated protein substrates forADP-ribosylation, which include histones, DNA metabolizing enzymes andPARP itself, are modified on surface glutamate residues. PARP catalyzesattachment of one ADP-ribose unit to the protein (initiation), followedby polymerization of as many as 200 ADP-ribose monomers (elongation) via2′-1″ glycosidic linkages. In addition, PARP catalyzes branching of thepolymer at a lower frequency.

[0003] The role of PARP in the DNA repair process is incompletelydefined. The binding of PARP to nicked double-stranded DNA is suggestedto facilitate the repair process by transiently blocking DNA replicationor recombination. The subsequent poly(ADP-ribosyl)ation of PARP andhistones may result in introduction of a substantial negative charge,causing repulsion of the modified proteins from the DNA. The chromatinstructure is then proposed to relax, enhancing the access of DNA repairenzymes to the site of damage.

[0004] Excessive activation of PARP in response to cell damage or stressis hypothesized to result in cell death (Sims et al. Biochemistry 1983,22, 5188; Yamamoto et al. Nature 1981, 294, 284). Activation of PARP byDNA strand breaks may be mediated by nitric oxide (NO) or variousreactive oxygen intermediates. When the degree of DNA damage is large,PARP may catalyze a massive amount of poly(ADP-ribosyl)ation, depletingthe cell's levels of NAD⁺. As the cell attempts to maintain homeostasisby resynthesizing NAD⁺, levels of ATP may decrease precipitously (sincesynthesis of one molecule of NAD⁺ requires four molecules of ATP) andthe cell may die through depletion of its energy stores.

[0005] Activation of PARP has been reported to play a role in cell deathin a number of disease states, suggesting that PARP inhibitors wouldhave therapeutic efficacy in those conditions. Enhancedpoly(ADP-ribosyl)ation has been observed following focal cerebralischemia in the rat, consistent with activation of PARP in stroke(Tokime et al. J. Cereb. Blood Flow Metab. 1998, 18, 991). A substantialbody of published pharmacological and genetic data supports thehypothesis that PARP inhibitors would be neuroprotective followingcerebral ischemia, or stroke. Inhibitors of PARP protected against NMDA-or NO-induced neurotoxicity in rat cerebral cortical cultures (Zhang etal., Science 1994, 263, 687; Eliasson et al. Nature Med. 1997, 3, 1089).The degree of neuroprotection observed for the series of compoundsdirectly paralleled their activity as PARP inhibitors.

[0006] Inhibitors of PARP may also display neuroprotective efficacy inanimal models of stroke. The potent PARP inhibitor DPQ(3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone) (Suto etal., U.S. Pat. No. 5,177,075) provided a 54% reduction in infarct volumein a rat model of focal cerebral ischemia (permanent MCAo and 90 minbilateral occlusion of the common carotid artery) following i.p. dosing(10 mg/kg) two hours prior to and two hours after the initiation ofischemia (Takahashi et al. Brain Res. 1997, 829, 46).Intracerebroventricular administration of a less potent PARP inhibitor,3-aminobenzamide (3-AB), yielded a 47% decrease in infarct volume inmice following a two hour occlusion of the MCA by the suture threadmethod (Endres et al. J. Cereb. Blood Flow Metab. 1997, 17, 1143).Treatment with 3-AB also enhanced functional recovery 24 hours afterischemia, attenuated the decrease in NAD⁺ levels in ischemic tissues,and decreased the synthesis of poly(ADP-ribose) polymers as determinedby immunohistochemistry. Similarly, 3-AB (10 mg/kg) significantlyreduced infarct volume in a suture occlusion model of focal ischemia inthe rat (Lo et al. Stroke 1998,5 29, 830). The neuroprotective effect of3-AB (3-30 mg/kg, i.c.v.) was also observed in a permanent middlecerebral artery occlusion model of ischemia in the rat (Tokime et al. J.Cereb. Blood Flow Metab. 1998, 18, 991).

[0007] The availability of mice in which the PARP gene has been renderednon-functional (Wang, Genes Dev. 1995, 9, 509) has also helped tovalidate the role of PARP in neurodegeneration. Neurotoxicity due toNMDA, NO, or oxygen-glucose deprivation was virtually abolished inprimary cerebral cortical cultures from PARP^(−/−) mice (Eliasson et al.Nature Med. 1997, 3, 1089). In the mouse suture thread model ofischemia, an 80% reduction in infarct volume was observed in PARP^(−/−)mice, and a 65% reduction was noted in PARP^(+/−) mice. In Endres et al.(1997), there was reported a 35% reduction in infarct volume inPARP^(−/−) mice and a 31% reduction in PARP^(+/−) animals. In additionto neuroprotection, PARP^(−/−) mice demonstrated an improvement inneurological score and displayed increased NAD⁺ levels followingischemia.

[0008] Preclinical evidence also exists which suggests that PARPinhibitors may be efficacious in the treatment of Parkinson's disease.This is because loss of dopaminergic neurons in the substantia nigra isa hallmark of Parkinson's disease. Treatment of experimental animals orhumans with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) replicates the loss of dopaminergic neurons and the motorsymptoms of Parkinson's disease. MPTP activates PARP in the substantianigra, and mice lacking PARP are resistant to the neurodegenerativeeffects of MPTP (Mandir et al. Proc. Nat. Acad. Sci. 1999, 96, 5774).Similarly, the PARP inhibitor 3-aminobenzamide is reported to attenuatethe loss of NAD⁺ in the striatum following administration of MPTP tomice (Cosi et al. Brain Res. 1998, 809, 58).

[0009] Activation of PARP has been implicated in the functional deficitsthat may result from traumatic brain injury and spinal cord injury. In acontrolled cortical impact model of traumatic brain injury, PARP^(−/−)mice displayed significantly improved motor and cognitive function ascompared to PARP^(+/+) mice (Whalen et al. J. Cereb. Blood Flow Metab.1999, 19, 835). Peroxynitrite production and PARP activation have alsobeen demonstrated in spinal cord-injured rats (Scott et al. Ann. Neurol.1999, 45, 120). These results suggest that inhibitors of PARP mayprovide protection from loss of function following head or spinaltrauma.

[0010] The role of PARP as a mediator of cell death following ischemiaand reperfusion may not be limited to the nervous system. In thisconnection, a recent publication reported that a variety of structurallydistinct PARP inhibitors, including 3-AB and related compounds, reduceinfarct size following cardiac ischemia and reperfusion in the rabbit(Thiemermann et al. Proc. Nat. Acad. Sci. 1997, 94, 679). In theisolated perfused rabbit heart model, inhibition of PARP reduced infarctvolume and contractile dysfunction following global ischemia andreperfusion. Skeletal muscle necrosis following ischemia and reperfusionwas also attenuated by PARP inhibitors. Similar cardioprotective effectsof 3-AB in a rat myocardial ischemia/reperfusion model were reported byZingarelli and co-workers (Zingarelli et al. Cardiovascular Research1997, 36, 205). These in vivo results are further supported by data fromexperiments in cultured rat cardiac myocytes (Gilad et al. J. Mol. CellCardiol. 1997, 29, 2585). Inhibitors of PARP (3-AB and nicotinamide)protected the myocytes from the reductions in mitochondrial respirationobserved following treatment with oxidants such as hydrogen peroxide,peroxynitrite, or nitric oxide donors. The genetic disruption of PARP inmice was recently demonstrated to provide protection delayed cellularinjury and production of inflammatory mediators following myocardialischemia and reperfusion (Yang et al. Shock 2000, 13, 60). These datasupport the hypothesis that administration of a PARP inhibitor couldcontribute to a positive outcome following myocardial infarction. Aparticularly useful application of a PARP inhibitor might involveadministration concurrent with a treatment designed to reperfuse theaffected area of the heart, including angioplasty or a clot-dissolvingdrug such as tPA.

[0011] The activity of PARP is also implicated in the cellular damagethat occurs in a variety of inflammatory diseases. Activation ofmacrophages by pro-inflammatory stimuli may result in the production ofnitric oxide and superoxide anion, which combine to generateperoxynitrite, resulting in formation of DNA single-strand breaks andactivation of PARP. The role of PARP as a mediator of inflammatorydisease is supported by experiments employing PARP^(−/−) mice orinhibitors of PARP in a number of animal models. For example, joints ofmice subjected to collagen-induced arthritis contain nitrotyrosine,consistent with generation of peroxynitrite (Szabo et al. J. Clin.Invest. 1998, 100, 723). The PARP inhibitor5-iodo-6-amino-1,2-benzopyrone reduced the incidence and severity ofarthritis in these animals, decreasing the severity of necrosis andhyperplasia of the synovium as indicated by histological examination. Inthe carrageenan-induced pleurisy model of acute local inflammation, 3-ABinhibited the histological injury, pleural exudate formation andmononuclear cell infiltration characteristic of the inflammatory process(Cuzzocrea et al Eur. J. Pharmacology 1998, 342, 67).

[0012] Results from rodent models of colitis suggest that PARPactivation may be involved in the pathogenesis of inflammatory boweldisease (Zingarelli et al. Gastroenterology 1999, 116, 335).Administration of trinitrobenzene sulfonic acid into the lumen of thebowel causes mucosal erosion, neutrophil infiltration, and theappearance of nitrotyrosine. Deletion of the PARP gene or inhibition ofPARP by 3-AB decreased tissue damage and attenuated neutrophilinfiltration and nitrotyrosine formation, suggesting that PARPinhibitors may be useful in the treatment of inflammatory bowel disease.

[0013] A role for PARP in the pathogenesis of endothelial dysfunction inmodels of endotoxic shock has also been proposed (Szabo et al. J. Clin.Invest. 1997, 100, 723).

[0014] This is because PARP inhibition or genetic deletion of PARP mayprotect against the decrease in mitochondrial respiration that occursfollowing treatment of endothelial cells with peroxynitite.

[0015] The activation of PARP is involved in the induction ofexperimental diabetes initiated by the selective beta cell toxinstreptozocin (SZ). Substantial breakage of DNA may be induced by SZ,resulting in the activation of PARP and depletion of the cell's energystores as described above in Yamamoto et al.(1981). In cells derivedfrom PARP^(−/−) mice, exposure to reactive oxygen intermediates resultsin attenuated depletion of NAD⁺ and enhanced cell viability relative towild-type cells (Heller et al. J. Biol. Chem. 1995, 270, 11176). Similareffects were observed in wild-type cells treated with 3-AB. Subsequentstudies in mice treated with SZ indicated that deletion of the PARP geneprovides protection against loss of beta cells (Burkart et al. NatureMed. 1999, 5, 314; Pieper et al. Proc. Nat. Acad. Sci. 1999, 96, 3059).These observations support the hypothesis that an inhibitor of PARP mayhave therapeutic utility in the treatment of type I diabetes.

[0016] Another potential therapeutic utility of PARP inhibitors involvesenhancement of the anti-tumor activity of radiation or DNA-damagingchemotherapeutic agents (Griffin et al. Biochemie 1995, 77, 408). SincepolyADP-ribosylation occurs in response to these treatments and is partof the DNA repair process, a PARP inhibitor might be expected to providea synergistic effect.

[0017] Like PARP, protein kinases play a critical role in the control ofcells. In particular, kinases are known to be involved in cell growthand differentiation. Aberrant expression or mutations in protein kinaseshave been shown to lead to uncontrolled cell proliferation, such asmalignant tumor growth, and various defects in developmental processes,including cell migration and invasion, and angiogenesis. Protein kinasesare therefore critical to the control, regulation, and modulation ofcell proliferation in diseases and disorders associated with abnormalcell proliferation. Protein kinases have also been implicated as targetsin central nervous system disorders such as Alzheimer's disease,inflammatory disorders such as psoriasis, bone diseases such asosteoporosis, atherosclerosis, restenosis, thrombosis, metabolicdisorders such as diabetes, and infectious diseases such as viral andfungal infections.

[0018] One of the most commonly studied pathways involving kinaseregulation is cellular signaling from receptors at the cell surface tothe nucleus. Generally, the pattern of expression, ligand availability,and the array of downstream signal transduction pathways that areactivated by a particular receptor, determine the function of eachreceptor. One example of a pathway includes a cascade of kinases inwhich members of the growth factor receptor tyrosine kinases deliversignals via phosphorylation to other kinases such as Src tyrosinekinase, and the Raf, Mek and Erk serine/threonine kinase families. Eachof these kinases is represented by several family members that playrelated but functionally distinct roles. The loss of regulation of thegrowth factor signaling pathway is a frequent occurrence in cancer aswell as other disease states (Fearon, Genetic Lesions in Human Cancer,Molecular Oncology 1996, 143-178).

[0019] One receptor tyrosine kinase signaling pathway includes thevascular endothelial growth factor (VEGF) receptor kinase. It has beenshown that binding of VEGF to the receptor VEGFR2 affects cellproliferation. For instance, binding of VEGF to the VEGFR-2/flt-1receptor, which is expressed primarily on endothelial cells, results inreceptor dimerization and initiation of a complex cascade which resultsin growth of new blood vessels (Korpelainen and Alitalo, Curr. Opin.Cell. Biol. 1998, 10, 159). Suppression of formation of new bloodvessels by inhibition of the VEGFR tyrosine kinases would have utilityin a variety of diseases, including treatment of solid tumors, diabeticretinopathy and other intraocular neovascular syndromes, maculardegeneration, rheumatoid arthritis, psoriasis, and endometriosis.

[0020] An additional kinase signal transduction is the stress-activatedprotein kinase (SAPK) pathway (Ip and Davis Curr. Opin. Cell Biol. 1998,10, 205). In response to stimuli such as cytokines, osmotic shock, heatshock, or other environmental stress, the pathway is activated and dualphosphorylation of Thr and Tyr residues within a Thr-Pro-Tyr motif ofthe c-jun N-terminal kinases (JNKs) is observed. Phosphorylationactivates the JNKs for subsequent phosphorylation and activation ofvarious transcription factors, including c-Jun, ATF2 and ELK-1.

[0021] The JNKs are mitogen-activated protein kinases (MAPKs) that areencoded by three distinct genes, jnk1,jnk2 and jnk3, which can bealternatively spliced to yield a variety of different JNK isoforms(Gupta et al., EMBO J 1996, 15, 2760). The isoforms differ in theirability to interact with and phosphorylate their target substrates.Activation of JNK is performed by two MAPK kinases (MAPKK), MKK4 andMKK7. MKK4 is an activator of JNK as well as an additional MAPK, p38,while MKK7 is a selective activator of JNK. A number of MAPKK kinasesare responsible for activation of MKK4 and MKK7, including the MEKKfamily and the mixed lineage kinase, or MLK family. The MLK family iscomprised of six members, including MLK1, MLK2, MLK3, MLK6, dual leucinezipper kinase (DLK) and leucine zipper-bearing kinase (LZK). MLK2 isalso known as MST (Katoh, et al. Oncogene, 1994, 10, 1447). Multiplekinases are proposed to be upstream of the MAPKKKs, including but notrestricted to germinal center kinase (GCK), hematopoietic progenitorkinase (HPK), and Rac/cdc42. Specificity within the pathway iscontributed, at least in part, by scaffolding proteins that bindselected members of the cascade. For example the JNK interactingprotein-1 (JIP-1) binds HPK1, DLK or MLK3, MKK7 and JNK, resulting in amodule which enhances JNK activation (Dickens et al. Science 1997, 277,693).

[0022] Manipulation of the activity of the SAPK pathway can have a widerange of effects, including promotion of both cell death and cellsurvival in response to various pro-apoptotic stimuli. For example,down-regulation of the pathway by genetic disruption of the geneencoding JNK3 in the mouse provided protection against kainicacid-induced seizures and prevented apoptosis of hippocampal neurons(Yang et al. Nature 1997, 389, 865). Similarly, inhibitors of the JNKpathway such as JIP-1 inhibit apoptosis (Dickens, supra). In contrast,the activity of the JNK pathway appears to be protective in someinstances. Thymocytes in which MKK4 has been deleted display increasedsensitivity to CD95- and CD3 mediated apoptosis (Nishina et al. Nature1997, 385, 350). Overexpression of MLK3 leads to transformation of NIH3T3 fibroblasts (Hartkamp et al. Cancer Res. 1999, 59, 2195).

[0023] An area the present invention is directed toward isidentification of compounds that modulate the MLK members of the SAPKpathway and promote either cell death or cell survival. Inhibitors ofMLK family members would be anticipated to lead to cell survival anddemonstrate therapeutic activity in a variety of diseases, includingchronic neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and Huntington's disease and acute neurologicalconditions such as cerebral ischemia, traumatic brain injury and spinalinjury. Inhibitors of MLK members leading to inhibition of the SAPKpathway (JNK activity) would also display activity in inflammatorydiseases and cancer.

[0024] An additional member of the MAP kinase family of proteins is thep38 kinase. Activation of this kinase has been implicated in theproduction of proinflammatory cytokines such as IL-1 and TNF. Inhibitionof this kinase could therefore offer a treatment for disease states inwhich disregulated cytokine production is involved.

[0025] The signals mediated by kinases have also been shown to controlcell growth, cell death and differentiation in the cell by regulatingthe processes of the cell cycle. A family of kinases called cyclindependent kinases (CDKS) controls progression through the eukaryoticcell cycle. The loss of control of CDK regulation is a frequent event inhyperproliferative diseases and cancer.

[0026] Inhibitors of kinases involved in mediating or maintainingparticular disease states represent novel therapies for these disorders.Examples of such kinases include Src, raf, the cyclin-dependent kinases(CDK) 1, 2, and 4 and the checkpoint kinases Chk1 and Cds1 in cancer,CDK2 or PDGF-R kinase in restenosis, CDK5 and GSK3 kinases inAlzheimer's Disease, c-Src kinase in osteoporosis, GSK3 kinase in type-2diabetes, p38 kinase in inflammation, VEGFR 1-3 and TIE-1 and -2 kinasesin angiogenesis, UL97 kinase in viral infections, CSF-1R kinase in boneand hematopoietic diseases, and Lck kinase in autoimmune diseases andtransplant rejection.

[0027] A variety of compounds which are described as PARP or kinaseinhibitors have been reported in the literature including Banasik et al.J. Biol. Chem. 1992, 267, 1569 and Banasik et al. Mol. Cell. Biochem.1994, 138, 185. Many other PARP inhibiting compounds have been thesubject of patents. For example, compounds that are described as PARPinhibitors are disclosed in WO 99/08680, WO 99/11622, WO 99/11623, WO99/11624, WO 99/11628, WO 99/11644, WO 99/11645, WO 99/11649, WO99/59973, WO 99/59975 and U.S. Pat. No. 5,587,384.

[0028] Structurally related compounds, which are described as havingactivities other than PARP inhibition, are disclosed in WO 99/47522, EP0695755, and WO 96/28447. Other structurally related compounds, theirsyntheses and precursors are disclosed in Piers et al. J. Org. Chem.2000, 65, 530, Berlinck et al. J. Org. Chem. 1998, 63, 9850, McCort etal. Tetrahedron Lett. 1999, 40, 6211, Mahboobi et al. Tetrahedron 1996,52, 6363, Rewcastle et al. J. Med. Chem. 1996, 39, 918, Harris et al.Tetrahedron Lett. 1993, 34, 8361, Moody et al. J. Org. Chem. 1992, 57,2105, Ohno et al. Heterocycles 1991, 32, 1199, Eitel et al. J. Org.Chem. 1990, 55, 5368, Krutosikova et al. Coll. Czech. Chem. Commun.1988, 53, 1770, Muchowski et al. Tetrahedron Lett. 1987, 28, 3453, Joneset al. J. Chem. Soc., Perkin Trans. 11984, 2541, Noland et al. J. Org.Chem. 1983, 48, 2488, Jones et al. J. Org. Chem. 1980, 45, 4515, Leonardet al. J. Am. Chem. Soc. 1976, 98, 3987, Rashidan et al. Arm. Khim. Zh.1968, 21, 793, Abrash et al. Biochemistry 1965, 4, 99, U.S. Pat. Nos.5,728,709, 4,912,107, EP 0768311, JP 04230385, WO 99/65911, WO 99/41276,WO 98/09967, and WO 96/11933.

[0029] Because of the potential role in therapeutically treatingneurodegenerative disorders, cancers, and other PARP and kinase relateddiseases, PARP and kinase inhibitors are an important class of compoundsrequiring further discovery, exploration, and development. Although, awide variety of PARP and kinase inhibitors are known, many suffer fromproblems such as toxicity, poor solubility, and limited efficacy, whichprevent practical therapeutic use and preclude further development intoeffective drugs. Thus, there is a current and immediate need for newPARP and kinase inhibitors for the treatment of PARP and kinase relateddiseases. The present invention is directed to this, as well as otherimportant ends.

SUMMARY OF THE INVENTION

[0030] The present invention is directed, in part, to novel multicycliccompounds. Specifically, in one embodiment, there are provided compoundsof formula I:

[0031] wherein constituent members of formula I are disclosed in detail,infra.

[0032] Another aspect of the invention relates to compounds of formulaIa:

[0033] wherein constituent members of formula Ia are disclosed indetail, infra.

[0034] Another aspect of the invention relates to multicyclic compoundsof formula IIa:

[0035] wherein constituent members of formula IIaa are disclosed indetail, infra.

[0036] A further aspect of the invention relates to compounds of formulaIIaa:

[0037] wherein constituent members of formula IIaa are disclosed indetail, infra.

[0038] In yet another embodiment of the present invention, there areprovided multicyclic compounds of formula IIb:

[0039] wherein constituent members of formula IIb are disclosed indetail, infra.

[0040] In yet another embodiment of the present invention, there areprovided multicyclic compounds of formula IIbb:

[0041] wherein constituent members of formula IIb are disclosed indetail, infra.

[0042] In an additional embodiment of the invention, there are providedcompounds of formula III:

[0043] wherein constituent members of formula III are disclosed indetail, infra.

[0044] In an additional embodiment of the invention, there are providedcompounds of formula IIIa:

[0045] wherein constituent members of formula IIa are disclosed indetail, infra.

[0046] In still another embodiment of the invention, there are providedcompounds of formula IV:

[0047] wherein constituent members of formula IV are disclosed indetail, infra.

[0048] In a further embodiment of the invention, there are providedcompounds of formula IVa:

[0049] wherein constituent members of formula IVa are disclosed indetail, infra.

[0050] The present invention further encompasses a method of inhibitingPARP, VEGFR2, or MLK3 activity comprising contacting said PARP, VEGFR2,or MLK3 with a compound of formula I:

[0051] wherein:

[0052] each of A and B is, independently,

[0053] C(═O), CH(OR³), CH(SR³),

[0054] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0055] C(═O)NR³, N═CR³,

[0056] SO, or SO₂;

[0057] Y and Z, together with the carbon atoms to which they areattached, form:

[0058] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0059] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0060] a C₃ to C₅ heteroaryl group;

[0061] each of E and F is, independently,

[0062] lower alkyl; or

[0063] E and F, together with the atoms to which they are attached,form:

[0064] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0065] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0066] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0067] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0068] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0069] R² is:

[0070] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0071] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0072] each of R³ and R⁴ is, independently,

[0073] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0074] G is:

[0075] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0076] J is:

[0077] J³-(J²)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0078] each of J¹ and J² is, independently,

[0079] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0080] J³ is:

[0081] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0082] In yet another aspect of the present invention, a method isprovided for treating or preventing a neurodegenerative diseasecomprising administering to a mammal a therapeutically effective amountof a compound of formula I:

[0083] wherein:

[0084] each of A and B is, independently,

[0085] C(═O), CH(OR³), CH(SR³),

[0086] CH₂, CH³, CHR³CHR⁴, CR³R⁴,

[0087] C(═O)NR³, N═CR³,

[0088] SO, or SO₂;

[0089] Y and Z, together with the carbon atoms to which they areattached, form:

[0090] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0091] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0092] a C₃ to C₅ heteroaryl group;

[0093] each of E and F is, independently,

[0094] lower alkyl; or

[0095] E and F, together with the atoms to which they are attached,form:

[0096] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0097] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0098] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0099] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0100] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0101] R² is:

[0102] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0103] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0104] each of R³ and R⁴ is, independently,

[0105] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0106] G is:

[0107] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0108] J is:

[0109] J³-(J²)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0110] each of J¹ and J² is, independently,

[0111] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0112] J³ is:

[0113] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0114] In a further aspect of the present invention, a method isprovided for treating traumatic central nervous system injuries orpreventing neuronal degradation associated with traumatic centralnervous system injuries comprising administering to a mammal atherapeutically effective amount of a compound of formula I:

[0115] wherein:

[0116] each of A and B is, independently,

[0117] C(═O), CH(OR³), CH(SR³),

[0118] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0119] C(═O)NR³, N═CR³,

[0120] SO, or SO₂;

[0121] Y and Z, together with the carbon atoms to which they areattached, form:

[0122] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0123] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0124] a C₃ to C₅ heteroaryl group;

[0125] each of E and F is, independently,

[0126] lower alkyl; or

[0127] E and F, together with the atoms to which they are attached,form:

[0128] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0129] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0130] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0131] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0132] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0133] R² is:

[0134] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0135] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0136] each of R³ and R⁴ is, independently,

[0137] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0138] G is:

[0139] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0140] J is:

[0141] J³-(J²)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0142] each of J¹ and J² is, independently,

[0143] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0144] J³ is:

[0145] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0146] In another aspect of the present invention, a method is providedfor treating cerebral ischemia, cardiac ischemia, inflammation,endotoxic shock, or diabetes comprising administering to a mammal apharmaceutically effective amount of a compound of formula I:

[0147] wherein:

[0148] each of A and B is, independently,

[0149] C(═O), CH(OR³), CH(SR³),

[0150] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0151] C(═O)NR³, N═CR³,

[0152] SO, or SO₂;

[0153] Y and Z, together with the carbon atoms to which they areattached, form:

[0154] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0155] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0156] a C₃ to C₅ heteroaryl group;

[0157] each of E and F is, independently,

[0158] lower alkyl; or

[0159] E and F, together with the atoms to which they are attached,form:

[0160] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0161] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0162] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0163] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0164] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0165] R² is:

[0166] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0167] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0168] each of R³ and R⁴ is, independently,

[0169] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0170] G is:

[0171] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0172] J is:

[0173] J³-(J²)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0174] each of J¹ and J² is, independently,

[0175] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0176] J³ is:

[0177] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0178] In a yet a further aspect of the present invention, a method isprovided for suppressing the formation of blood vessels in a mammalcomprising administering to a mammal a pharmaceutically effective amountof a compound of formula I:

[0179] wherein:

[0180] each of A and B is, independently,

[0181] C(═O), CH(OR³), CH(SR³),

[0182] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0183] C(═O)NR³, N═CR³,

[0184] SO, or SO₂;

[0185] Y and Z, together with the carbon atoms to which they areattached, form:

[0186] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0187] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0188] a C₃ to C₅ heteroaryl group;

[0189] each of E and F is, independently,

[0190] lower alkyl; or

[0191] E and F, together with the atoms to which they are attached,form:

[0192] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0193] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0194] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0195] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0196] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0197] R² is:

[0198] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0199] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0200] each of R³ and R⁴ is, independently,

[0201] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0202] G is:

[0203] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR2SO₂, or NR³SO₂;

[0204] J is:

[0205] J³-(J³)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0206] each of J¹ and J² is, independently,

[0207] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0208] J³ is:

[0209] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0210] In a further aspect of the present invention, a method isprovided for treating cellular proliferative disorders comprisingadministering to a mammal a pharmaceutically effective amount of acompound of formula I:

[0211] wherein:

[0212] each of A and B is, independently,

[0213] C(═O), CH(OR³), CH(SR³),

[0214] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0215] C(═O)NR³, N═CR³,

[0216] SO, or SO₂;

[0217] Y and Z, together with the carbon atoms to which they areattached, form:

[0218] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0219] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0220] a C₃ to C₅ heteroaryl group;

[0221] each of E and F is, independently,

[0222] lower alkyl; or

[0223] E and F, together with the atoms to which they are attached,form:

[0224] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0225] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0226] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0227] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0228] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0229] R² is:

[0230] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0231] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0232] each of R³ and R⁴ is, independently,

[0233] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0234] G is:

[0235] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0236] J is:

[0237] J³-(J²)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0238] each of J¹ and J² is, independently,

[0239] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0240] J³ is:

[0241] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0242] In yet another aspect of the present invention, a method fortreating cancer comprising administering to a mammal a pharmaceuticallyeffective amount of a compound of formula I:

[0243] wherein:

[0244] each of A and B is, independently,

[0245] C(═O), CH(OR³), CH(SR³),

[0246] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0247] C(═O)NR³, N═CR³,

[0248] SO, or SO₂;

[0249] Y and Z, together with the carbon atoms to which they areattached, form:

[0250] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0251] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0252] a C₃ to C₅ heteroaryl group;

[0253] each of E and F is, independently,

[0254] lower alkyl; or

[0255] E and F, together with the atoms to which they are attached,form:

[0256] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0257] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0258] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0259] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0260] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J;

[0261] R² is:

[0262] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0263] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0264] each of R³ and R⁴ is, independently,

[0265] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0266] G is:

[0267] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0268] J is:

[0269] J³-(J²)_(n)-(J¹)_(m) wherein each n and m is, independently, 0 or1;

[0270] each of J¹ and J² is, independently,

[0271] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0272] J³ is:

[0273] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid.

[0274] The present invention further encompasses a method of inhibitingPARP, VEGFR2, or MLK3 activity comprising contacting said PARP, VEGFR2,or MLK3 with compounds of formula Ia:

[0275] wherein:

[0276] each of A and B is, independently,

[0277] C(═O), CH(OR³), CH(SR³),

[0278] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0279] C(═O)NR³, N═CR³,

[0280] SO, or SO₂;

[0281] Y and Z, together with the carbon atoms to which they areattached, form:

[0282] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0283] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0284] a C₃ to C₅ heteroaryl group;

[0285] each of E and F is, independently, lower alkyl; or

[0286] E and F, together with the atoms to which they are attached,form:

[0287] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0288] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0289] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0290] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0291] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0292] R² is:

[0293] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0294] each of R³ and R⁴ is, independently,

[0295] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0296] G is:

[0297] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0298] J is:

[0299] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0300] each of J¹ and J² is, independently,

[0301] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0302] J³ is:

[0303] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0304]  any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

[0305] In yet another aspect of the present invention, a method isprovided for treating or preventing a neurodegenerative diseasecomprising administering to a mammal a therapeutically effective amountof a compound of formula Ia:

[0306] wherein:

[0307] each of A and B is, independently,

[0308] C(═O), CH(OR³), CH(SR³),

[0309] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0310] C(═O)NR³, N═CR³,

[0311] SO, or SO₂;

[0312] Y and Z, together with the carbon atoms to which they areattached, form:

[0313] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0314] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0315] a C₃ to C₅ heteroaryl group;

[0316] each of E and F is, independently,

[0317] lower alkyl; or

[0318] E and F, together with the atoms to which they are attached,form:

[0319] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0320] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0321] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0322] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0323] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0324] R² is:

[0325] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0326] each of R³ and R⁴ is, independently,

[0327] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0328] G is:

[0329] O, S, SO, SO₂, NR², NR, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0330] J is:

[0331] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0332] each of J¹ and J² is, independently,

[0333] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0334] J³ is:

[0335] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0336] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

[0337] In a further aspect of the present invention, a method isprovided for treating traumatic central nervous system injuries orpreventing neuronal degradation associated with traumatic centralnervous system injuries comprising administering to a mammal atherapeutically effective amount of a compound of formula Ia:

[0338] wherein:

[0339] each of A and B is, independently,

[0340] C(═O), CH(OR³), CH(SR³),

[0341] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0342] C(═O)NR³, N═CR³,

[0343] SO, or SO₂;

[0344] Y and Z, together with the carbon atoms to which they areattached, form:

[0345] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0346] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0347] a C₃ to C₅ heteroaryl group;

[0348] each of E and F is, independently,

[0349] lower alkyl; or

[0350] E and F, together with the atoms to which they are attached,form:

[0351] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0352] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0353] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0354] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0355] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0356] R² is:

[0357] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0358] each of R³ and R⁴ is, independently,

[0359] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0360] G is:

[0361] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0362] J is:

[0363] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0364] each of J¹ and J² is, independently,

[0365] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0366] J³ is:

[0367] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0368] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

[0369] In another aspect of the present invention, a method is providedfor treating cerebral ischemia, cardiac ischemia, inflammation,endotoxic shock, or diabetes comprising administering to a mammal apharmaceutically effective amount of a compound of formula Ia:

[0370] wherein:

[0371] each of A and B is, independently,

[0372] C(═O), CH(OR³), CH(SR³),

[0373] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0374] C(═O)NR³, N═CR³,

[0375] SO, or SO₂;

[0376] Y and Z, together with the carbon atoms to which they areattached, form:

[0377] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0378] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0379] a C₃ to C₅ heteroaryl group;

[0380] each of E and F is, independently,

[0381] lower alkyl; or

[0382] E and F, together with the atoms to which they are attached,form:

[0383] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0384] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0385] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0386] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0387] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0388] R² is:

[0389] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0390] each of R³ and R⁴ is, independently,

[0391] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0392] G is:

[0393] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0394] J is:

[0395] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0396] each of J¹ and J² is, independently,

[0397] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0398] J³ is:

[0399] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0400] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

[0401] In a yet a further aspect of the present invention, a method isprovided for suppressing the formation of blood vessels in a mammalcomprising administering to a mammal a pharmaceutically effective amountof a compound of formula Ia:

[0402] wherein:

[0403] each of A and B is, independently,

[0404] C(═O), CH(OR³), CH(SR³),

[0405] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0406] C(═O)NR³, N═CR³,

[0407] SO, or SO₂;

[0408] Y and Z, together with the carbon atoms to which they areattached, form:

[0409] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0410] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0411] a C₃ to C₅ heteroaryl group;

[0412] each of E and F is, independently,

[0413] lower alkyl; or

[0414] E and F, together with the atoms to which they are attached,form:

[0415] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0416] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0417] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0418] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0419] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0420] R² is:

[0421] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0422] each of R³ and R⁴ is, independently,

[0423] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0424] G is:

[0425] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, Or NR³SO₂;

[0426] J is:

[0427] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0428] each of J¹ and J² is, independently,

[0429] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0430] J³ is:

[0431] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0432] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

[0433] In a further aspect of the present invention, a method isprovided for treating cellular proliferative disorders comprisingadministering to a mammal a pharmaceutically effective amount of acompound of formula Ia:

[0434] wherein:

[0435] each of A and B is, independently,

[0436] C(═O), CH(OR³), CH(SR³),

[0437] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0438] C(═O)NR³, N═CR³,

[0439] SO, or SO₂;

[0440] Y and Z, together with the carbon atoms to which they areattached, form:

[0441] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0442] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0443] a C₃ to C₅ heteroaryl group;

[0444] each of E and F is, independently,

[0445] lower alkyl; or

[0446] E and F, together with the atoms to which they are attached,form:

[0447] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0448] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0449] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0450] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0451] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0452] R² is:

[0453] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0454] each of R³ and R⁴ is, independently,

[0455] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0456] G is:

[0457] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0458] J is:

[0459] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0460] each of J¹ and J² is, independently,

[0461] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0462] J³ is:

[0463] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0464] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

[0465] In yet another aspect of the present invention, a method fortreating cancer comprising administering to a mammal a pharmaceuticallyeffective amount of a compound of formula Ia:

[0466] wherein:

[0467] each of A and B is, independently,

[0468] C(═O), CH(OR³), CH(SR³),

[0469] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0470] C(═O)NR³, N═CR³,

[0471] SO, or SO₂;

[0472] Y and Z, together with the carbon atoms to which they areattached, form:

[0473] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0474] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0475] a C₃ to C₅ heteroaryl group;

[0476] each of E and F is, independently,

[0477] lower alkyl; or

[0478] E and F, together with the atoms to which they are attached,form:

[0479] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0480] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0481] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0482] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0483] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0484] R² is:

[0485] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0486] each of R³ and R⁴ is, independently,

[0487] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0488] G is:

[0489] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0490] J is:

[0491] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0492] each of J¹ and J² is, independently,

[0493] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0494] J³ is:

[0495] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0496] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2.

BRIEF DESCRIPTION OF THE DRAWINGS

[0497]FIG. 1 shows a schematic including a compound within the scope ofthe present invention and precursors thereto.

[0498]FIG. 2 shows a general synthetic strategy for preparing compoundswithin the scope of the present invention.

[0499]FIG. 3 shows another general synthetic strategy for preparingcompounds within the scope of the present invention.

[0500]FIG. 4 shows yet another general synthetic strategy for preparingcompounds within the scope of the present invention.

[0501]FIG. 5 shows still another general synthetic strategy forpreparing compounds within the scope of the present invention.

[0502]FIG. 6 shows yet another general synthetic strategy for preparingcompounds within the scope of the present invention.

[0503]FIG. 7 shows a synthetic strategy for preparing benzimidazolederivatives within the scope of the present invention.

[0504]FIG. 8 shows a synthetic strategy for preparing compounds withinthe scope of the invention.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0505] The present invention is directed, in part, to new multicycliccompounds that may be highly useful in connection with the inhibition ofPARP, VEGFR2, MLK3, or other enzymes. The new compounds are described inmore detail below.

[0506] Specifically, in one embodiment, the present invention relates tonovel multicyclic compounds of formula I:

[0507] wherein:

[0508] each of A and B is, independently,

[0509] C(═O), CH(OR³), CH(SR³),

[0510] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0511] C(═O)NR³, N═CR³,

[0512] SO, or SO₂;

[0513] Y and Z, together with the carbon atoms to which they areattached, form:

[0514] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0515] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0516] a C₃ to C₅ heteroaryl group;

[0517] each of E and F is, independently,

[0518] lower alkyl; or

[0519] E and F, together with the atoms to which they are attached,form:

[0520] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0521] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0522] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0523] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0524] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0525] R² is:

[0526] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0527] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0528] each of R³ and R⁴ is, independently,

[0529] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0530] G is:

[0531] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0532] J is:

[0533] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0534] each of J¹ and J² is, independently,

[0535] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0536] J³ is:

[0537] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid;

[0538] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O),and Y and Z, together with the atoms to which they are attached, formunsubstituted indol-2,3-diyl, and R² is hydrogen, then E and F, togetherwith the atoms to which they are attached, form a group other thanunsubstituted imidazole or N-methylimidazole.

[0539] In another embodiment, the present invention provides compoundsof formula Ia:

[0540] wherein:

[0541] each of A and B is, independently,

[0542] C(═O), CH(OR³), CH(SR³),

[0543] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0544] C(═O)NR³, N═CR³,

[0545] SO, or SO₂;

[0546] Y and Z, together with the carbon atoms to which they areattached, form:

[0547] a substituted or unsubstituted aryl group, wherein said arylgroup is monocyclic or bicyclic and said substituted aryl group has atleast one substituent J;

[0548] a substituted or unsubstituted bicyclic heteroaryl group, whereinsaid substituted bicyclic heteroaryl group has at least one substituentJ; or

[0549] a C₃ to C₅ heteroaryl group;

[0550] each of E and F is, independently,

[0551] lower alkyl; or

[0552] E and F, together with the atoms to which they are attached,form:

[0553] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0554] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0555] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0556] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0557] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0558] R is:

[0559] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0560] each of R³ and R⁴ is, independently,

[0561] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0562] G is:

[0563] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0564] J is:

[0565] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0566] each of J¹ and J² is, independently,

[0567] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, a protected amino acid,aminocarbonyloxy, arylaminocarbonyloxy, or heteroarylaminocarbonyloxy;and

[0568] J³ is:

[0569] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0570] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2;

[0571] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O),and Y and Z, together with the atoms to which they are attached, formunsubstituted indol-2,3-diyl, and R² is hydrogen, then E and F, togetherwith the atoms to which they are attached, form a group other thanunsubstituted imidazole or N-methylimidazole.

[0572] In other preferred embodiments, the present invention includescompounds of formula I or Ia where E and F combined together with thecarbon atoms to which they are attached, form a C₅ cycloalkyl group.

[0573] In a preferred embodiment of the present invention, there areprovided multicyclic compounds of formula IIa:

[0574] wherein:

[0575] each of A and B is, independently,

[0576] C(═O), CH(OR³), CH(SR³),

[0577] CH₂, CHR³, CHR³CHR⁴, CR³R⁴,

[0578] C(═O)NR³, N═CR³,

[0579] SO, or SO₂;

[0580] each of E and F is, independently,

[0581] lower alkyl; or

[0582] E and F, together with the carbon atoms to which they areattached, form:

[0583] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0584] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0585] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0586] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0587] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0588] G is:

[0589] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂;

[0590] R¹ is:

[0591] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0592] R² is:

[0593] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0594] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0595] each of R³ and R⁴ is, independently,

[0596] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0597] J is:

[0598] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0599] each of J¹ and J² is, independently, carbonyl, loweralkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, or a protected amino acid; and

[0600] J³ is:

[0601] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid;

[0602] each of D¹ and D² is, independently,

[0603] N(X¹), N(X²), C(R¹)(X¹), C(R¹)(X²), C(═O), S, or O; and

[0604] each of X¹ and X² is, independently,

[0605] hydrogen, halo, group J, lower alkyl, lower alkyl having at leastone substituent J, substituted or unsubstituted C₃ to C₇ cycloalkylwherein said substituted cycloalkyl group has at least one substituentJ, substituted or unsubstituted C₂ to C₆ heterocycloalkyl wherein saidsubstituted heterocycloalkyl group has at least one substituent J,substituted or unsubstituted aryl wherein said substituted aryl grouphas at least one substituent J, substituted or unsubstituted heteroarylwherein said substituted heteroaryl group has at least one substituentJ; or

[0606] X¹ and X², together with the atoms to which they are attached,form:

[0607] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0608] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one substituent J; or

[0609] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one substituent J.

[0610] In a preferred embodiment of the present invention, there areprovided multicyclic compounds of formula IIaa:

[0611] wherein:

[0612] each of A and B is, independently, C(═O), CH(OR³), CH(SR³), CH₂,CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂;

[0613] each of E and F is, independently,

[0614] lower alkyl; or

[0615] E and F, together with the carbon atoms to which they areattached, form:

[0616] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0617] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0618] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0619] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0620] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0621] G is:

[0622] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0623] R is:

[0624] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0625] R² is:

[0626] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0627] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0628] each of R³ and R⁴ is, independently,

[0629] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J;

[0630] J is:

[0631] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0632] each of J¹ and J² is, independently,

[0633] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0634] J³ is:

[0635] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0636] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2;

[0637] each of D¹ and D² is, independently,

[0638] N(X¹), N(X²), C(R¹)(X¹), C(R¹)(X²), C(═O), S, or O; and

[0639] each of X¹ and X² is, independently,

[0640] hydrogen, halo, group J, lower alkyl, lower alkyl having at leastone substituent J, substituted or unsubstituted C₃ to C₇ cycloalkylwherein said substituted cycloalkyl group has at least one substituentJ, substituted or unsubstituted C₂ to C₆ heterocycloalkyl wherein saidsubstituted heterocycloalkyl group has at least one substituent J,substituted or unsubstituted aryl wherein said substituted aryl grouphas at least one substituent J, substituted or unsubstituted heteroarylwherein said substituted heteroaryl group has at least one substituentJ; or

[0641] X¹ and X², together with the atoms to which they are attached,form: a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J; asubstituted or unsubstituted aryl group wherein said substituted arylgroup has at least one substituent J; or a substituted or unsubstitutedheteroaryl group wherein said substituted heteroaryl group has at leastone substituent J.

[0642] Preferred embodiments of the present invention include compoundsof formula IIa or IIaa wherein:

[0643] each of A and B is, independently,

[0644] C(═O), CH₂, CH(OR³), or CH(SR³); and

[0645] E and F, together with the atoms to which they are attached,form:

[0646] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0647] a substituted or unsubstituted C₃ to C₅ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J; or

[0648] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising within at least one group G wherein saidsubstituted heterocycloalkyl group comprising G has at least onesubstituent J; and G is O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³,NR³SO₂, or NR³SO₂.

[0649] Preferred embodiments of the present invention include compoundsof formula IIa or IIaa wherein:

[0650] each of A and B is, independently,

[0651] C(═O), CH₂, CH(OR³), or CH(SR³); and

[0652] E and F, together with the atoms to which they are attached,form:

[0653] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0654] a substituted or unsubstituted heteroaryl group, wherein saidsubstituted heteroaryl group has at least one group J.

[0655] In an alternate preferred embodiment of the present invention,there are provided compounds of formula IIb:

[0656] wherein:

[0657] each of A and B is, independently,

[0658] C(═O), CH(OR³), CH(SR³), CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³,N═CR³, SO, or SO₂;

[0659] each of E and F is, independently,

[0660] lower alkyl; or

[0661] E and F, together with the carbon atoms to which they areattached, form:

[0662] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0663] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0664] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0665] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0666] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0667] G is:

[0668] O, S, SO, SO₂, NR², NR¹, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂;

[0669] R² is:

[0670] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0671] R² is:

[0672] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J; formyl; acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0673] each of R³ and R⁴ is, independently,

[0674] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0675] J is:

[0676] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0677] each of J¹ and J² is, independently,

[0678] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0679] J³ is:

[0680] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid;

[0681] each of D¹ and D² is, independently,

[0682] C(X¹), C(X²), or N; and

[0683] each of X¹ and X² is, independently,

[0684] hydrogen, halo, group J, lower alkyl, lower alkyl having at leastone substituent J, substituted or unsubstituted C₃ to C₇ cycloalkylwherein said substituted cycloalkyl group has at least one substituentJ, substituted or unsubstituted C₂ to C₆ heterocycloalkyl wherein saidsubstituted heterocycloalkyl group has at least one substituent J,substituted or unsubstituted aryl wherein said substituted aryl grouphas at least one substituent J, substituted or unsubstituted heteroarylwherein said substituted heteroaryl group has at least one substituentJ; or

[0685] X¹ and X², together with the atoms to which they are attached,form: a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J; asubstituted or unsubstituted aryl group wherein said substituted arylgroup has at least one substituent J; or a substituted or unsubstitutedheteroaryl group wherein said substituted heteroaryl group has at leastone substituent J;

[0686] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O),and D¹ and D² are C(X¹) or C(X²) in which X¹ and X², together with theatoms to which they are attached, form unsubstituted phenyl, and R² ishydrogen, then E and F, together with the atoms to which they areattached, form a group other than unsubstituted imidazole orN-methylimidazole.

[0687] In an alternate preferred embodiment of the present invention,there are provided compounds of formula IIbb:

[0688] wherein:

[0689] each of A and B is, independently,

[0690] C(═O), CH(OR³), CH(SR³), CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³,N═CR³, SO, or SO₂;

[0691] each of E and F is, independently,

[0692] lower alkyl; or

[0693] E and F, together with the carbon atoms to which they areattached, form:

[0694] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0695] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0696] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising at least one group G wherein said substitutedheterocycloalkyl group comprising G has at least one substituent J;

[0697] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0698] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0699] G is:

[0700] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂;

[0701] R¹ is:

[0702] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0703] R² is:

[0704] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0705] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0706] each of R³ and R⁴ is, independently,

[0707] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0708] J is:

[0709] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0710] each of J¹ and J² is, independently,

[0711] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0712] 3 is:

[0713] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0714] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2;

[0715] each of D¹ and D² is, independently,

[0716] C(X¹), C(X²), or N; and

[0717] each of X¹ and x² is, independently,

[0718] hydrogen, halo, group J, lower alkyl, lower alkyl having at leastone substituent J, substituted or unsubstituted C₃ to C₇ cycloalkylwherein said substituted cycloalkyl group has at least one substituentJ, substituted or unsubstituted C₂ to C₆ heterocycloalkyl wherein saidsubstituted heterocycloalkyl group has at least one substituent J,substituted or unsubstituted aryl wherein said substituted aryl grouphas at least one substituent J, substituted or unsubstituted heteroarylwherein said substituted heteroaryl group has at least one substituentJ; or

[0719] X¹ and X², together with the atoms to which they are attached,form:

[0720] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0721] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one substituent J; or

[0722] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one substituent J;

[0723] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O),and D¹ and D² are C(X¹) or C(X²) in which X¹ and X², together with theatoms to which they are attached, form unsubstituted phenyl, and R² ishydrogen, then E and F, together with the atoms to which they areattached, form a group other than unsubstituted imidazole orN-methylimidazole.

[0724] Preferred embodiments of the present invention include compoundsof formula IIb or IIbb wherein:

[0725] A is C(═O), CH₂, CH(OR³), or CH(SR³);

[0726] B is C(═O); and

[0727] each E and F is, independently,

[0728] CH₃; or

[0729] E and F, together with the carbon atoms to which they areattached, form a C₅ cycloalkyl group.

[0730] Other preferred embodiments of the present invention includecompounds of formula IIb or IIbb wherein:

[0731] A is C(═O);

[0732] B is CH₂; and

[0733] E and F, together with the carbon atoms to which they areattached, form a C₅ cycloalkyl group.

[0734] Additional preferred embodiments of the present invention includecompounds of formula IIb or IIbb wherein:

[0735] each A and B is, independently,

[0736] C(═O), CH₂, CH(OR³), or CH(SR³); and

[0737] E and F, together with the atoms to which they are attached,form:

[0738] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0739] a substituted or unsubstituted C₃ to C₅ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0740] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising within at least one group G wherein saidsubstituted heterocycloalkyl group comprising G has at least onesubstituent J.

[0741] Group G is as defined previously.

[0742] Further preferred embodiments of the present invention includecompounds of formula IIb or IIbb wherein:

[0743] each A and B is, independently,

[0744] C(═O), CH₂, CH(OR³), or CH(SR³); and

[0745] E and F, together with the atoms to which they are attached,form:

[0746] a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or

[0747] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0748] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O), D¹and D² are C(X¹) or C(X²) in which X¹ and X², together with the atoms towhich they are attached, form unsubstituted phenyl, and R² is hydrogen,then E and F, together with the atoms to which they are attached, form agroup other than unsubstituted imidazole or N-methylimidazole.

[0749] In yet another embodiment of the invention, there are providedcompounds of formula III:

[0750] wherein:

[0751] each of A and B is, independently,

[0752] C(═O), CH(OR³), CH(SR³), CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³,N═CR³, SO, or SO₂;

[0753] each of E and F is, independently,

[0754] lower alkyl; or

[0755] E and F, together with the carbon atoms to which they areattached, form:

[0756] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0757] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0758] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising within the ring structure at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J;

[0759] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0760] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0761] G is:

[0762] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO²;

[0763] R¹ is:

[0764] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0765] R² is:

[0766] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0767] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0768] each of R³ and R⁴ is, independently,

[0769] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0770] J is:

[0771] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0772] each of J¹ and J² is, independently,

[0773] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0774] J³ is:

[0775] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, or aryl ester of phosphonicacid; and

[0776] each of X¹ and x² is, independently,

[0777] hydrogen, halo, group J, lower alkyl, lower alkyl having at leastone substituent J, substituted or unsubstituted C₃ to C₇ cycloalkylwherein said substituted cycloalkyl group has at least one substituentJ, substituted or unsubstituted C₂ to C₆ heterocycloalkyl wherein saidsubstituted heterocycloalkyl group has at least one substituent J,substituted or unsubstituted aryl wherein said substituted aryl grouphas at least one substituent J, substituted or unsubstituted heteroarylwherein said substituted heteroaryl group has at least one substituentJ; or

[0778] X¹ and X², together with the atoms to which they are attached,form:

[0779] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0780] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one substituent J; or

[0781] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one substituent J;

[0782] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O), X¹and X², together with the atoms to which they are attached, formunsubstituted phenyl, and R² is hydrogen, then E and F, together withthe atoms to which they are attached, form a group other thanunsubstituted imidazole or N-methylimidazole.

[0783] In a preferred embodiment, compounds of formula III have E and Fcombined together with the atoms to which they are attached to form a C₅cycloalkyl group.

[0784] In yet another embodiment of the invention, there are providedcompounds of formula IIIa:

[0785] wherein:

[0786] each of A and B is, independently,

[0787] C(═O), CH(OR³), CH(SR³), CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³,N═CR³, SO, or SO₂;

[0788] each of E and F is, independently,

[0789] lower alkyl; or

[0790] E and F, together with the carbon atoms to which they areattached, form:

[0791] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0792] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0793] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising within the ring structure at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J;

[0794] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0795] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0796] G is:

[0797] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0798] R¹ is:

[0799] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0800] R² is:

[0801] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0802] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0803] each of R⁵ and R⁴ is, independently,

[0804] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0805] J is:

[0806] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0807] each of J¹ and J² is, independently,

[0808] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0809] J³ is:

[0810] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0811] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2; and

[0812] each of X¹ and X² is, independently,

[0813] hydrogen, halo, group J, lower alkyl, lower alkyl having at leastone substituent J, substituted or unsubstituted C₃ to C₇ cycloalkylwherein said substituted cycloalkyl group has at least one substituentJ, substituted or unsubstituted C₂ to C₆ heterocycloalkyl wherein saidsubstituted heterocycloalkyl group has at least one substituent J,substituted or unsubstituted aryl wherein said substituted aryl grouphas at least one substituent J,

[0814] substituted or unsubstituted heteroaryl wherein said substitutedheteroaryl group has at least one substituent J; or

[0815] X¹ and X², together with the atoms to which they are attached,form:

[0816] a substituted or unsubstituted C₄ to C₇ cycloalkyl group whereinsaid substituted cycloalkyl group has at least one substituent J;

[0817] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one substituent J; or

[0818] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one substituent J;

[0819] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O), X¹and X², together with the atoms to which they are attached, formunsubstituted phenyl, and R² is hydrogen, then E and F, together withthe atoms to which they are attached, form a group other thanunsubstituted imidazole or N-methylimidazole.

[0820] In a preferred embodiment, compounds of formula IIIa have E and Fcombined together with the atoms to which they are attached to form a C₅cycloalkyl group.

[0821] Additional preferred embodiments of the compounds of formula IIIor IIIa include those where X¹ and X² are a substituted or unsubstitutedheteroaryl group wherein said substituted heteroaryl group has at leastone substituent J.

[0822] Further preferred embodiments of the compounds of formula III orIIIa include those where A and B are, independently C(═O) or CH₂.

[0823] Other preferred embodiments include compounds of formula III orIIIa, wherein groups E and F, when taken together with the atoms towhich they are attached, form a C₅ cycloalkyl group; X¹ and X² are asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one substituent J; and A and B are,independently C(═O) or CH₂. More preferably, X¹ and X² are a substitutedor unsubstituted pyridyl or pyrimidyl group, wherein said substitutedpyridyl or pyrimidyl group has at least one substituent J; and A and Bare C(═O).

[0824] In still another embodiment of the invention, there are providedcompounds of formula IV:

[0825] wherein:

[0826] each of A and B is, independently,

[0827] C(═O), CH(OR³), CH(SR³), CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³,N═CR³, SO, or SO₂;

[0828] each of E and F is, independently,

[0829] lower alkyl; or

[0830] E and F, together with the carbon atoms to which they areattached, form:

[0831] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0832] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0833] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising within at least one group G wherein saidsubstituted heterocycloalkyl group comprising G has at least onesubstituent J;

[0834] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0835] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0836] G is:

[0837] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂;

[0838] V is N(R¹), O, or S;

[0839] R¹ is:

[0840] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0841] R² is:

[0842] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J; formyl; acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid;

[0843] each of R³ and R⁴ is, independently,

[0844] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0845] J is:

[0846] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0847] each of J³ and J² is, independently,

[0848] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0849] J³ is: hydrogen, halo, hydroxy, thio, cyano, sulfonic acid,carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonicacid, lower alkyl, lower alkyl ester of phosphonic acid, or aryl esterof phosphonic acid;

[0850] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O), Vis NH, J and R² are hydrogen, then E and F, together with the atoms towhich they are attached, form a group other than unsubstituted imidazoleor N-methylimidazole.

[0851] In still another embodiment of the invention, there are providedcompounds of formula IVa:

[0852] wherein:

[0853] each of A and B is, independently,

[0854] C(═O), CH(OR³), CH(SR³), CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³,N═CR³, SO, or SO₂;

[0855] each of E and F is, independently,

[0856] lower alkyl; or

[0857] E and F, together with the carbon atoms to which they areattached, form:

[0858] a substituted or unsubstituted C₄ to C₇ cycloalkyl group, whereinsaid substituted cycloalkyl group has at least one substituent J;

[0859] a substituted or unsubstituted C₃ to C₆ heterocycloalkyl groupwherein said substituted heterocycloalkyl group has at least onesubstituent J;

[0860] a substituted or unsubstituted heterocycloalkyl groupendocyclically comprising within at least one group G wherein saidsubstituted heterocycloalkyl group comprising G has at least onesubstituent J;

[0861] a substituted or unsubstituted aryl group wherein saidsubstituted aryl group has at least one group J; or

[0862] a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one group J;

[0863] G is:

[0864] O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂;

[0865] V is N(R¹), O, or S;

[0866] R¹ is:

[0867] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, lower arylsulfonyl, anamino acid, or a protected amino acid;

[0868] R² is:

[0869] hydrogen, lower alkyl, lower alkyl having at least onesubstituent J;

[0870] formyl; acetyl, lower alkanoyl, lower alkanoyl having at leastone substituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, ora protected amino acid;

[0871] each of R³ and R⁴ is, independently,

[0872] hydrogen, lower alkyl, aryl, lower alkyl having at least onesubstituent J, or aryl having at least one substituent J.

[0873] J is:

[0874] J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0or 1;

[0875] each of J¹ and J² is, independently,

[0876] carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and

[0877] J³ is:

[0878] hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl,lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, loweralkyl, lower alkyl ester of phosphonic acid, aryl ester of phosphonicacid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and

[0879] any two adjacent J groups can combine to form —X—(CH₂)_(p)—X—,wherein X is independently O or NH, and p is 1 or 2;

[0880] with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O), Vis NH, J and R² are hydrogen, then E and F, together with the atoms towhich they are attached, form a group other than unsubstituted imidazoleor N-methylimidazole.

[0881] Certain preferred embodiments include compounds of formula IV orIVa, wherein V is N(R¹); groups E and F, when taken together with theatoms to which they are attached, form a C₅ cycloalkyl group; and A andB are independently C(═O) or CH₂.

[0882] Further preferred embodiments include compounds of formula IV,that may be particularly important with regard to inhibition of PARP, inwhich A and B are both CO, R² and J are both H, E and F, together withthe atoms to which they are attached, form a cyclopentyl group, and V iseither NH (1a, see Table 1) or N-(Lysine 2 HCl )(1k, see Table 1).Additionally, the compound of formula IV wherein A and B are both CO, R²is H, V is NH, E and F, together with the atoms to which they areattached, form a cyclopentyl group, and J is NH₂CH₂ 3-substituent (2p,see Table 2) comprises a further preferred embodiment.

[0883] Preferred embodiments of the present invention which may haveparticular relevance to the inhibition of VEGFR2 include compounds offormula IV in which both A and B are CO, E and F together are-CH═NCH═CH—, V is NH, R² is H, and J is either H (12a, see Table 5) or3-CH₃ (12n, see Table 5).

[0884] Additional preferred embodiments of the compounds describedherein include those where groups E and F, when taken together with theatoms to which they are attached, form a group other than imidazolyl.

[0885] Other preferred embodiments of the compounds described hereininclude those where groups E and F, when taken together with the atomsto which they are attached, form a C₅ cycloalkyl group. Furtherembodiments of the compounds described herein include those where X¹ andX² are a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one substituent J. Anotherpreferred embodiment of the compounds described herein include thosewhere A and B are, independently, C(═O) or CH₂.

[0886] Additional preferred embodiments of the compounds describedherein include those where groups E and F, when taken together with theatoms to which they are attached, form a C₅ cycloalkyl group; X¹ and X²are a substituted or unsubstituted heteroaryl group wherein saidsubstituted heteroaryl group has at least one substituent J; and A and Bare, independently C(═O) or CH₂.

[0887] The term “alkyl”, as used herein, unless otherwise specified,refers to a saturated straight, branched, or cyclic hydrocarbon of C₁ toC₂₀. Alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl,isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl,adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0888] The term “lower alkyl,” as used herein, and unless otherwisespecified, refers to a C₁ to C₆ saturated straight chain, branched, orcyclic hydrocarbon. Lower alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl,cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0889] The terms “cycloalkyl” and “C_(n) cycloalkyl” are meant to referto a monocyclic saturated or partially unsaturated hydrocarbon group.The term “C_(n)” in this context, wherein n is an integer, denotes thenumber of carbon atoms comprising the ring of the cycloalkyl group. Forinstance, C₆ cycloalkyl indicates a six-membered ring. The bondsconnecting the endocyclic carbon atoms of a cycloalkyl group may besingle or part of a fused aromatic moiety, so long as the cycloalkylgroup is not aromatic. Examples of cycloalkyl groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

[0890] The terms “heterocycloalkyl” or “C_(n) heterocycloalkyl” aremeant to refer to a monocyclic saturated or partially unsaturated cyclicradical which, besides carbon atoms, contains at least one heteroatom asring members. Typically, heteroatoms include, but are not limited to,oxygen, nitrogen, sulfur, selenium, and phosphorus atoms. In thiscontext, the term “C_(n),” wherein n is an integer, denotes the numberof carbon atoms comprising the ring, but is not indicative of the totalnumber of atoms in the ring. For example, C₄ heterocycloalkyl includesrings with five or more ring members, wherein four of the ring membersare carbon and the remaining ring members are heteroatoms. In addition,the bonds connecting the endocyclic atoms of a heterocycloalkyl groupmay be part of a fused aromatic moiety, so long as the heterocycloalkylgroup is not aromatic. Examples of heterocycloalkyl groups include, butare not limited to, 2-pyrrolidinyl, 3-pyrrolidinyl, piperdinyl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, and3-tetrahydrothienyl.

[0891] The term “aryl,” as used herein, and unless otherwise specified,refers to a mono-, di-, tri-, or multinuclear aromatic ring system.Non-limiting examples include phenyl, naphthyl, anthracenyl, andphenanthrenyl.

[0892] The term “heteroaryl,” as used herein, refers to an aromatic ringsystem that includes at least one heteroatom ring member. Non-limitingexamples are pyrryl, pyridinyl, furyl, pyridyl, 1,2,4-thiadiazolyl,pyrimidyl, thienyl, thiophenyl, isothiazolyl, imidazolyl, tetrazolyl,pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl,isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl,isoxazolyl, and acridinyl.

[0893] The term “aralkyl,” as used herein, is meant to refer toaryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, and diphenylethyl.

[0894] The term “lower aralkyl,” as used herein, is meant to refer toaryl-substituted lower alkyl radicals. Non-limiting examples includebenzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.

[0895] The term “aralkoxy,” as used herein, is meant to refer to thegroup RO— wherein R is an aralkyl group as defined above.

[0896] The term “lower aralkoxy,” as used herein, is meant to refer tothe group RO— wherein R is a lower aralkyl group as defined above.

[0897] The term “alkoxy,” as used herein, is meant to refer to RO—,wherein R is an alkyl group as defined above.

[0898] The term “lower alkoxy,” as used herein, is meant to refer toRO—, wherein R is a lower alkyl group as defined above. Non-limitingexamples include methoxy, ethoxy, and tert-butyloxy.

[0899] The term “aryloxy,” as used herein, is meant to refer to RO—,wherein R is an aryl group as defined above.

[0900] The terms “lower alkylamino” and “lower dialkylamino” refer to anamino group that bears one or two lower alkyl substituents,respectively.

[0901] The terms “amido” and “carbonylamino,” as used herein, are meantto refer to —C(O)N(H)—.

[0902] The term “alkylamido,” as used herein, is meant to refer to—C(O)NR— wherein R is an alkyl group as defined above.

[0903] The term “dialkylamido,” as used herein, is meant to refer to—C(O)NR′R″ wherein R′ and R″ are, independently, alkyl groups as definedabove.

[0904] The term “lower alkylamido,” as used herein, is meant to refer to—C(O)NR— wherein R is a lower alkyl group as defined above.

[0905] The term “lower dialkylamido,” as used herein, is meant to referto —C(O)NR′R″ wherein R′ and R″ are, independently, lower alkyl groupsas defined above.

[0906] The terms “alkanoyl” and “alkylcarbonyl,” as used herein, referto RC(O)— wherein R is an alkyl group as defined above.

[0907] The terms “lower alkanoyl” and “lower alkylcarbonyl” as usedherein, refer to RC(O)— wherein R is a lower alkyl group as definedabove. Non-limiting examples of such alkanoyl groups include acetyl,trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, and4-methylvaleryl.

[0908] The term “arylcarbonyl,” as used herein, refers to RC(O)— whereinR is an aryl group as defined above.

[0909] The term “aryloxycarbonyl,” as used herein, is meant to refer toROC(O)— wherein R is an aryl group as defined above.

[0910] The term “halo,” as used herein, refers to fluoro, chloro, bromo,or iodo.

[0911] The term “alkylsulfonyl,” as used herein, is meant to refer tothe group RSO₂— wherein R is an alkyl group as defined above.

[0912] The term “arylsulfonyl,” as used herein, is meant to refer to thegroup RSO₂— wherein R is an aryl group as defined above.

[0913] The term “alkyloxycarbonylamino,” as used herein, is meant torefer to the group ROC(O)N(H)— wherein R is an alkyl group as definedabove.

[0914] The term “lower alkyloxycarbonylamino,” as used herein, is meantto refer to the group ROC(O)N(H)— wherein R is a lower alkyl group asdefined above.

[0915] The term “aryloxycarbonylamino,” as used herein, is meant torefer to the group ROC(O)N(H)— wherein R is an aryl group as definedabove.

[0916] The term “sulfonylamido,” as used herein, is meant to refer tothe group —SO₂C(O)NH—.

[0917] The term “alkylsulfonylamido,” as used herein, is meant to referto the group RSO₂C(O)NH— wherein R is an alkyl group as defined above.

[0918] The term “arylsulfonylamido,” as used herein, is meant to referto the group RSO₂C(O)NH— wherein R is an aryl group as defined above.

[0919] The term “lower alkyl ester of phosphonic acid,” as used herein,is meant to refer to the group —P(O)(OR′)(OR″) wherein R′ and R″ arelower alkyl as defined above.

[0920] The term “aryl ester of phosphonic acid,” as used herein, ismeant to refer to the group —P(O)(OR′)(OR″) wherein R′ and R″ are arylas defined above.

[0921] The term “aminocarbonyloxy,” as used herein, is meant to refer tothe group RR′N—C(O)—O— wherein R and R′ are an alkyl group as definedabove.

[0922] The term “arylaminocarbonyloxy,” as used herein, is meant torefer to the group Ar—N(R)—C(O)—O— wherein Ar is aryl, as defined above,and R is an alkyl group as defined above.

[0923] The term “heteroarylaminocarbonyloxy,” as used herein, is meantto refer to the group het-Ar—N(R)—C(O)—O— wherein het-Ar is heteroaryl,as defined above, and R is an alkyl group as defined above.

[0924] As used herein, the term “amino acid” means a molecule containingboth an amino group and a carboxyl group. It includes an “α-amino acid”which is well known to one skilled in the art as a carboxylic acid thatbears an amino functionality on the carbon adjacent to the carboxylgroup. Amino acids can be naturally occurring or non-naturallyoccurring.

[0925] “Protected amino acids,” as used herein refer to amino acids, asdescribed above, comprising protecting groups. For example, the aminogroup of an amino acid may be protected with t-butoxycarbonyl orbenzyloxycarbonyl groups. In addition, the carboxyl group of the aminoacid may be protected as alkyl and aralkyl esters. Furthermore, alcoholgroups of amino acids can be protected as -alkyl ethers, aralkyl ethers,and silyl ethers.

[0926] The term “endocyclically comprising” is meant to describe acyclic chemical moiety that includes a specified chemical group as aring forming member. As an example, a furanyl group endocyclicallycomprises an oxygen atom because the oxygen atom is a member of the ringstructure. In the context of the present invention, groups E and F maybe combined together with the atoms to which they are attached to form aheterocycloalkyl group. This heterocycloalkyl group may endocyclicallycomprise the chemical group G, meaning that at least one atom of group Gis a ring forming member.

[0927] As a non-limiting example illustrated below, E and F may becombined together with the atoms to which they are attached to form theheterocycloalkyl group endocyclically comprising group G, wherein G, inthis instance, is N(CH₃).

[0928] As used herein, the term “therapeutically effective amount” ismeant to refer to an amount of compound of the present invention thatwill elicit a desired therapeutic or prophylactic effect or responsewhen administered according to the desired treatment regimen.

[0929] As used herein, the term “contacting” means bringing together,either directly or indirectly, one or more molecules with another,thereby facilitating intermolecular interactions. Contacting may occurin vitro, ex vivo, or in vivo.

[0930] As used herein, the term “cellular proliferative disorders” ismeant to refer to malignant as well as non-malignant cell populationswhich differ from the surrounding tissue both morphologically andgenotypically. Types of cellular proliferative disorders include, forexample, solid tumors, cancer, diabetic retinopathy, intraocularneovascular syndromes, macular degeneration, rheumatoid arthritis,psoriasis, and endometriosis.

[0931] All other terms used in the description of compounds of thepresent invention have their meaning as is well known in the art.

[0932] The present invention features methods for preparing themulticyclic compounds described herein which are useful as inhibitors ofPARP, VEGFR2, and MLK3. The method consists of a multistep synthesisstarting with the necessary heterocyclic compounds. For example, FIG. 1outlines the general synthesis of compounds of the present invention forthe case when the heterocyclic starting material is an indole.

[0933] Specifically, an indole A, which is unsubstituted or substitutedin positions 4-7 on the indole ring, is treated serially, for example,with butyllithium, carbon dioxide, t-butyllithium and a ketone B (havingsubstituents E and F) to provide a 2-substituted indolyl tertiaryalcohol C. This tertiary alcohol is eliminated, for example, underacidic conditions using hydrochloric acid or toluenesulfonic acid, toafford a substituted 2-vinylindole, D. Diels-Alder cycloaddition of Dwith a dienophile such as, but not limited to, maleimide (E) affords thecycloaddition intermediate F. Aromatization of the cycloadditionintermediate, for example, with oxygen in the presence of a catalystsuch as palladium or platinum or with an oxidant such as DDQ ortetrachloroquinone, produces carbazole G.

[0934] Further treatment of G with an alkylating or acylating reagentgives indole-N-substituted carbazole derivatives of the presentinvention as shown in FIG. 2.

[0935] Treatment of carbazole G (or the carbazole lactams in FIG. 5)with various electrophiles, such as R⁺, affords 3-substituted carbazolederivatives as shown in FIG. 3. In this manner, halogen or acyl groupscan be introduced, and the halogen can be displaced by variousnucleophiles including cyano, as shown in FIG. 5. The halogen can alsobe replaced by various alkyl, aryl, and heteroalkyl groups. The 3-cyanosubstituent can be reduced to give the 3-aminomethyl substituent whichcan be alkylated or acylated on the amino group.

[0936] When carbazole G contains bromoacetyl or substituted 2-bromoacylsubstituents, as shown in FIG. 4, the bromine can be displaced byvarious nucleophiles to give further embodiments of the presentinvention. Alternately, the 2-bromoacyl group may be reacted withvarious thioamides to give substituted thiazoles.

[0937] As discussed, using substituted indoles as starting materialaffords functionalized derivatives of G; however, an intramolecularWittig reaction can also be used to prepare substituted vinyl indoles D.Furthermore, dienophiles other than maleimide (E) may be used in theDiels-Alder reaction, and include for example, dialkyl fumarate, fumaricacid, dialkyl maleate, maleic acid, maleic anhydride, dialkylacetylenedicarboxylate or alkyl 3-cyanoacrylate. The intermediatesresulting from cycloaddition with these dienophiles give imides, or thecorresponding lactams as shown in FIG. 5. For example, anyhdrides,obtained from maleic anhydride cycloaddition or by dehydration ofdiacids, afford imides when treated with bis(trimethylsilyl)amine orurea. The anhydrides afford six-membered hydrazones when treated withhydrazine. The lactams are obtained by separating the cyano esterisomers, aromatizing each isomer, and reducing the cyano ester to thelactam, as shown in FIG. 5. Imides may also be reduced to lactams bywell established methods known to those skilled in the art.

[0938] Indole-type compounds of the present invention are preparedaccording to the scheme shown in FIG. 6. Here, substituted vinyl pyrrolestarting materials are prepared by the reaction of a pyrrole with anenamine of a ketone as described in the literature (Heterocycles 1974,2, 575-584). A substituted 2-vinyl pyrrole is reacted with variousdienophiles, such as those described above, to afford a cycloadditionintermediate which is a precursor to embodiments of the presentinvention. A nitrogen protecting group such as a silyl protecting group,particularly triisopropyl silyl, may used throughout as depicted in FIG.6.

[0939] Other heterocyclic precursors may be prepared by analogousreactions. For example, a substituted 5-vinyl imidazole is reacted withvarious dienophiles, such as those described above, to afford acycloaddition intermediate which can be further modified by reactionswell known to those skilled in the art to give benzimidazole precursors.Likewise, for example, a substituted 5-vinyl 1,2,3-triazole or 4-vinylthiazole can be reacted with various dienophiles as above to also affordcycloaddition intermediates leading to embodiments of the invention. Thebenzimidazole-type compounds of the present invention can also beprepared according to the method shown in FIG. 7, in which preformedbenzimidozoles serve as starting materials.

[0940] Furthermore, as shown in FIG. 8, an optionally substituted2-vinyl benzofuran or 2-vinyl benzothiophene can be reacted with variousdienophiles, such as those listed previously, to afford a cycloadditionintermediate. Modification of the cycloaddition intermediate can lead toimides, lactams, and related compounds of the present invention.

[0941] In certain preferred embodiments, the compounds of the presentinvention are PARP inhibitors. The potency of the inhibitor can betested by measuring PARP activity in vitro or in vivo. A preferred assaymonitors transfer of radiolabeled ADP-ribose units from [³²P]NAD⁺ to aprotein acceptor such as histone or PARP itself. Routine assays for PARPare disclosed in Purnell and Whish, Biochem. J. 1980, 185, 775,incorporated herein by reference.

[0942] In other preferred embodiments, the compounds of the presentinvention are also VEGFR2 or MLK3 inhibitors. The potency of theinhibitor can be tested by measuring VEGFR2 or MLK3 activity in vitro orin vivo. A preferred assay for VEGFR2 kinase activity involves thephosphorylation of a protein substrate immobilized on a microtiterplate. The resulting phosphotyrosine residue is detected with ananti-phosphotyrosine antibody conjugated to a europium chelate, allowingquantitation of the product by time-resolved fluorometry. Similar assaymethods have been employed for the detection of the tyrosine kinasec-src, as described in Braunwalder et al. Anal Biochem. 1996, 238, 159,incorporated herein by reference. A preferred assay method for MLK3utilizes phosphorylation of a protein substrate, such as myelin basicprotein, with [γ-³²P]ATP, followed by isolation of the acid-insoluble³²P-phosphoprotein product on a filtration plate. Analogous methods wereemployed for the assay of protein kinase C, as reported in Pitt and Lee,J. Biomol. Screening 1996, 1, 47, incorporated herein by reference.

[0943] Methods for the inhibition of PARP, VEGFR2, and MLK3 enzymeactivities are also contemplated by the present invention. Enzymeactivity can be reduced or inhibited by contacting the enzyme with atleast one compound described herein. The contacting can occur either invitro, in vivo, or ex vivo. Contacting can also be promoted by use ofcontacting media which enhances the rate of mixing of enzyme andinhibitor. Preferred media include water, water-based solutions,buffered solutions, water-miscible solvents, enzyme-solubilizingsolutions, and any combination thereof. Contacting cells containing theenzyme in vivo, preferably employs the inhibitor to be delivered inproximity to the enzyme associated with the cell in a biologicallycompatible medium. Preferred biologically compatible media includewater, water-based solutions, saline, biological fluids and secretions,and any other non-toxic material that may effectively deliver inhibitorto the vicinity of the enzyme in a biological system.

[0944] The compounds described herein can be used to prevent or treatthe onset or progression of any disease or condition related to PARPactivity in mammals, especially humans. Such conditions includetraumatic injury to the central nervous system, such as brain and spinalcord injuries, and the neuronal degradation associated with traumaticinjury to the central nervous system. Related conditions and diseasestreatable by methods of the present invention include vascular strokes,cardiac ischemia, cerebral ischemia, cerebrovascular disorders such asmultiple sclerosis, and neurodegenerative diseases such as Alzheimer's,Huntington's, and Parkinson's diseases. Other PARP related conditions ordiseases treatable by the compounds described herein includeinflammation such as pleurisy and colitis, endotoxic shock, diabetes,cancer, arthritis, cardiac ischemia, retinal ischemia, skin aging,chronic and acute pain, hemorrhagic shock, and others. For example,following the symptoms of a stroke, a patient can be administered one ormore compounds described herein to prevent or minimize damage to thebrain. Patients with symptoms of Alzheimer's, Huntington's, orParkinson's disease can be treated with compounds of the presentinvention to halt the progression of the disease or alleviate symptoms.PARP inhibitors may also be used to treat patients suffering fromcancer. For instance, cancer patients can be administered the presentcompounds in order to augment the anti-tumor effects of chemotherapy.

[0945] The compounds described herein can be used to prevent or treatthe progression of any disease or condition related to kinase activity(such as VEGFR2 or MLK3 activities) in mammals, especially humans. Forinstance, the compounds described herein may be used to treat conditionsrelated to MLK3 activity such as chronic neurodegenerative diseases as,for example, Alzheimer's disease, Parkinson's disease, and Huntington'sdisease, and acute neurological conditions such as cardiac ischemia,cerebral ischemia, as well as traumatic brain and spinal injuries.Further, the compounds described herein, can also be useful in thetreatment of inflammatory diseases and cancer related to MLK3 activity.Similarly, the compounds described herein, can be used to inhibit VEGFR2which may lead to suppression of formation of new blood vessels. Suchcompounds can therefore be useful in the treatment of conditionsassociated with new blood vessel formations such as, for example, solidtumors, diabetic retinopathy, and other intraocular neovascularsyndromes, macular degeneration, rheumatoid arthritis, psoriasis, andendometriosis.

[0946] The compounds described herein are preferably administered tomammals in a therapeutically effective amount. Dosage may vary dependingon the compound, the potency of the compound, the type of disease, andthe diseased state of the patient, among other variables. Dosage amountcan be measured by administration of pre-measured dosing means or unitdosages in the form of tablets, capsules, suppositories, powders,emulsions, elixirs, syrups, ointments, creams, or solutions.

[0947] In therapeutic or prophylactic use, PARP or kinase inhibitors maybe administered by any route that drugs are conventionally administered.Such routes of administration include intraperitoneal, intravenous,intramuscular, subcutaneous, intrathecal, intracheal, intraventricular,oral, buccal, rectal, parenteral, intranasal, transdermal orintradermal. Administration may be systemic or localized.

[0948] Compounds described herein may be administered in pure form,combined with other active ingredients, or combined withpharmaceutically acceptable nontoxic excipients or carriers. Oralcompositions will generally include an inert diluent carrier or anedible carrier. Pharmaceutically compatible binding agents, and/oradjuvant materials can be included as part of the composition. Tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a dispersing agent such as alginic acid, Primogel,or corn starch; a lubricant such as magnesium stearate; a glidant suchas colloidal silicon dioxide; a sweetening agent such as sucrose orsaccharin; or a flavoring agent such as peppermint, methyl salicylate,or orange flavoring. When the dosage unit form is a capsule, it cancontain, in addition to material of the above type, a liquid carriersuch as a fatty oil. In addition, dosage unit forms can contain variousother materials that modify the physical form of the dosage unit, forexample, coatings of sugar, shellac, or enteric agents. Further, a syrupmay contain, in addition to the active compounds, sucrose as asweetening agent and certain preservatives, dyes, colorings, andflavorings.

[0949] Alternative preparations for administration include sterileaqueous or nonaqueous solutions, suspensions, and emulsions. Examples ofnonaqueous solvents are dimethylsulfoxide, alcohols, propylene glycol,polyethylene glycol, vegetable oils such as olive oil and injectableorganic esters such as ethyl oleate. Aqueous carriers include mixturesof alcohols and water, buffered media, and saline. Intravenous vehiclesinclude fluid and nutrient replenishers, electrolyte replenishers, suchas those based on Ringer's dextrose, and the like. Preservatives andother additives may also be present such as, for example,antimicrobials, anti-oxidants, chelating agents, inert gases, and thelike.

[0950] Preferred methods of administration of the present compounds tomammals include intraperitoneal injection, intramuscular injection, andintravenous infusion. Various liquid formulations are possible for thesedelivery methods, including saline, alcohol, DMSO, and water basedsolutions. The concentration of inhibitor may vary according to dose andvolume to be delivered and can range from about 1 to about 1000 mg/mL.Other constituents of the liquid formulations can include,preservatives, inorganic salts, acids, bases, buffers, nutrients,vitamins, or other pharmaceuticals such as analgesics or additional PARPand kinase inhibitors. Particularly preferred formulations foradministration of the present compounds are detailed in the followingpublications that describe administration of known PARP inhibitors andare incorporated herein by reference in their entireties; Kato, T. etal. Anticancer Res. 1988, 8(2), 239, Nakagawa, K. et al. Carcinogenesis1988, 9, 1167, Brown, D. M. et al. Int. J. Radiat.

[0951] Oncol. Biol. Phys. 1984, 1665, Masiello, P. et al. Diabetologia1985, 28(9), 683, Masiello, P. et al. Res. Commun. Chem. Pathol.Pharmacol. 1990, 69(1), 17, Tsujiuchi, T. et al. Jpn. J Cancer Res.1992, 83(9), 985, and Tsujiuchi, T. et. al Jpn. J Cancer Res. 1991,82(7), 739.

[0952] Compounds of the present invention also may take the form of apharmacologically acceptable salt, hydrate, solvate, or metabolite.Pharmacologically acceptable salts include basic salts of inorganic andorganic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid,tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid,maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelicacid and the like. When compounds of the invention include an acidicfunction, such as a carboxy group, then suitable pharmaceuticallyacceptable cation pairs for the carboxy group are well known to thoseskilled in the art and include alkaline, alkaline earth, ammonium,quaternary ammonium cations and the like.

[0953] Those skilled in the art will appreciate that numerous changesand modifications can be made to the preferred embodiments of theinvention and that such changes and modifications can be made withoutdeparting from the spirit of the invention. It is, therefore, intendedthat the appended claims cover all such equivalent variations as fallwithin the true spirit and scope of the invention.

EXAMPLES Example 1 Measurement of PARP Enzymatic Activity

[0954] PARP activity was monitored by transfer of radiolabeledADP-ribose units from [³²P]NAD⁺ to a protein acceptor such as histone orPARP itself. The assay mixtures contained 100 mM Tris (pH 8.0), 2 mMDTT, 10 mM MgCl₂, 20 ug/ml DNA (nicked by sonication), 20 mg/ml histoneH1, 5 ng recombinant human PARP, and inhibitor or DMSO (<2.5% (v/v)) ina final volume of 100 uL. The reactions were initiated by the additionof 100 μM NAD⁺ supplemented with 2 uCi [³²P]NAD⁺/mL and maintained atroom temperature for 12 minutes. Assays were terminated by the additionof 100 μM of 50% TCA and the radiolabeled precipitate was collected on a96-well filter plate (Millipore, MADP NOB 50), washed with 25% TCA. Theamount of acid-insoluble radioactivity, corresponding topolyADP-ribosylated protein, was quantitated in a Wallac MicroBetascintillation counter.

Example 2 Measurement of VEGFR2 Kinase Enzymatic Activity

[0955] A 96-well FluoroNUNC MaxiSorp plate was coated with 100 μL/wellof recombinant human PLC-γ/GST substrate solution at a concentration of40 μg/mL in Tris-buffered saline (TBS). The VEGFR2 activity was assayedin a 100 μL assay mixture containing 50 mM HEPES (pH 7.4), 30 μM ATP, 10mM MnCl₂, 0.1% BSA, 2% DMSO, and 150 ng/mL recombinant humanbaculovirus-expressed human VEGFR2 cytoplasmic domain (prephosphorylatedfor 60 min at 4° C. in the presence of 30 μM ATP and 10 mM MnCl₂ priorto use). The kinase reaction was allowed to proceed at 37° C. for 15min. The europium-labeled anti-phosphotyrosine detection antibody wasadded at 1:5000 dilution in block buffer (3% BSA in TBST). After 1 hourof incubation at 37° C., 100 μL of enhancement solution (Wallac#1244-105) was added and the plate was gently agitated. After 5 min, thetime-resolved fluorescence of the resulting solution was measured usingthe BMG PolarStar (Model #403) using excitation and emission wavelengthsof 340 nm and 615 nm, respectively, a collection delay of 400 μsec andan integration time of 400 μsec.

Example 3 Measurement of MLK3 Enzymatic Activity

[0956] The activity assay for MLK3 was performed in MilliporeMultiscreen plates. Each 50 μL assay mixture contained 50 mM HEPES (pH7.0), 1 mM EGTA, 10 mM MgCl₂, 1 mM DTT, 25 mM β-glycerophosphate, 100 μMATP, 1 μCi [γ-³²P]ATP, 0.1% BSA, 500 μg/mL myelin basic protein, 2%DMSO, various concentrations of test compounds, and 2 μg/mL ofbaculoviral human GST-MLK1 kinase domain. Samples were incubated for 15min at 37° C. The reaction was stopped by adding ice-cold 50% TCA andthe proteins were allowed to precipitate for 30 min at 4° C. The plateswere allowed to equilibrate for 1-2 hours prior to counting in theWallac MicroBeta 1450 Plus scintillation counter.

Example 4 Determination of IC₅₀ for Inhibitors

[0957] Single-point inhibition data were calculated by comparing PARP,VEGFR2, or MLK3 activity in the presence of inhibitor to activity in thepresence of DMSO only. Inhibition curves for compounds were generated byplotting percent inhibition versus log₁₀ of the concentration ofcompound. IC₅₀ values were calculated by nonlinear regression using thesigmoidal dose-response (variable slope) equation in GraphPad Prism asfollows:

y=bottom+(top−bottom)/(1+10^((logIC) ^(₅₀) ^(−x)*Hillslope))

[0958] where y is the % activity at a given concentration of compound, xis the logarithm of the concentration of compound, bottom is the %inhibition at the lowest compound concentration tested, and top is the %inhibition at the highest compound concentration examined. The valuesfor bottom and top were fixed at 0 and 100, respectively. IC₅₀ valueswere reported as the average of at least three separate determinations.

[0959] The following Examples 5 to 10 present PARP, VECGFR2, and MLK3inhibiting data for compounds of the present invention. IC₅₀ values weredetermined as described in Examples 1 and 2. For some compounds,inhibiting data is presented as percent inhibition at a specifiedconcentration. Compounds are tabulated together with compound number,substituents, and enzyme inhibition data.

Example 5 PARP inhibiting data for compounds 1a to 1v of Formula IVwherein B is CO, R² is H, J is H, V is NR¹ and E and F, together withthe atoms to which they are attached, form a cyclopentyl group. A and R¹vary as listed below

[0960] TABLE 1 No. A R¹ PARP IC₅₀ (nM) 1a CO H  36 1b CO (CH₂)₃OCH₂Ph720 1c CO (CH₂)₃CN 38% @ 10 μM 1d CO (CH₂)₃Cl 64% @ 10 μM 1e CO (CH₂)₃OH946 1f CO (CH₂)₃-piperidine 68% @ 10 μM 1g CO (CH₂)₃-morpholine 67% @ 10μM 1h CO (CH₂)₃—NEt₂ 819 1i CO (CH₂)₄—NHCOCH₃ 10% @ 10 μM 1j CO SO₂Ph250 1k CO Lysine (2 HCl)  22 1l CO P-Alanine (HCl) 160 1m CO Glycine(HCl)  38 1n CO (CH₂)₂OCH₂Ph 1600  1o CO (CH₂)₂NEt₂ 12% @ 10 μM 1p COCH₂COOCH₂Ph 14% @ 10 μM 1q CO CH₂COOH 52% @ 10 μM 1r CO CH₂CONH₂ 63% @10 μM 1s CO CH₂-phthalimide 25% @ 10 μM 1t CH₂ CH₃ 800 1u CH₂ (BOC)₂Lys1500  1v CH₂ Lys 1400 

Example 6 PARP inhibiting data for compounds 2a to 5g of formula IVwherein B is CO, R² is H, V is NH, and E and F, together with the atomsto which they are attached, form a cyclopentyl group. A and J vary aslisted below

[0961] TABLE 2 PARP No. A J (3-Substituent) IC₅₀ (nM) 2a CO Br 25 2b COCl 39 2c CO F 39 2d CO CH₃CO 17 2e CO BrCH₂CO 13 2f CO CH₃BrCHCO 21 2gCO N-Methylpiperizino-CH₂CO 16 2h CO Morpholino-CH₂CO 13 2i COPiperidino-CH₂CO 20 2j CO Diethylamino-CH₂CO 21 2k COtBuO₂CCH₂N(CH₃)CH₂CO 19 2l CO HO₂CCH₂N(CH₃)CH₂CO  8 2m CO HO₂CCH₂CH₂CO 3 2n CO 1,2,4-Triazol-2-ylCH₂CO 15 2o CO CN 14 2p CO NH₂CH₂ 13 2q COHexahydrocyclopent[a]pyrrolo[3,4-c] 167  carbazole-7(6H)-one-3-NHCH₂ 2rCO CH₃CONHCH₂ 13 2s CO CH₃CH₂CONHCH₂ 28 2t CO CH₃CH₂CH₂CONHCH₂ 44 2u COBenzoyl-NHCH₂ 37 2v CO BOC-NHCH₂CONHCH₂ 33 2w CO BOC-NH(CH₂)₃CONHCH₂ 332x CO H₂NCH₂CONHCH₂ 45 2y CO H₂N(CH₂)₃CONHCH₂ 54 2z COCH₃O₂C(CH₂)₂CONHCH₂ 10 2aa CO CH₃O₂C(CH₂)₃CONHCH₂  9 2ab COHO₂C(CH₂)₂CONHCH₂ 50 2ac CO HO₂C(CH₂)₃CONHCH₂ 48 2ad CO BOC-NHCH₂ 93 2aeCO SO₃H  8 2af CH₂ Cl 120  2ag CH₂ CO₂H 80 2ah CH₂ CO₂CH₃ 59 2ai CH₂CONHCH₂CH₂NMe₂ 165  2aj CH₂ CONHCH₂CH₂NC₄H₈O 162  2ak CH₂ CONC₄H₈O 832al CH₂ CON(CH₃)CH₂(4-Pyr) 65 2am CH₂ CON(CH₃)CH₂CH₂(1-imidazole) 161 2an CH₂ CON(CH₃)CH₂(2-Pyr) 237  2ao CO OH 27 2ap CO OCH₃ 32 2aq COOCH₂CH₂OCH₂CH₃ 59 2ar CO OCH₂CH₂NEt₂ 88 2as CO OCH₂CH₂CH₂NMe₂ 100  2atCO OCH₂CH₂NC₄H₈O 22 2au CO OAc 33 2av CO CHO 29 2aw CO CH₂OH 22 2ax COCHOHCH₃ 102  2ay CH— H 408  OH 2az CO CH₂CH₃ 116  2ba CO COCO₂CH₃ 12 2bbCO COCO₂H  5 2bc CO CH₂CN 24 2bd CO CO₂H 85 2be CO CH₂CH₂NH₂ 36 2bf COCH₃ 82 2bg CO CH₂OCOCH₂NMe₂ 31 2bh CO CONH₂ 31 2bi CO CO₂CH₃ 27 2bj COCH₂NMe₂ 29 2bk CO CH₂NHEt 32 2bl CO CH₂N^(n)Pr 16 2bm CO CH₂NEt₂ 17 2bnCO CH₂N^(n)Bu₂ 28 2bo CO CH₂N(CH₂Ph)₂ 293  2bp CO CH₂NH^(n)Bu 25 2bq COCH₂NHCH₂Ph 26 2br CO CH₂N^(i)Pr 25 2bs CO CH₂N^(i)Pr₂ 25 2bt CO CH₂NHMe25 2bu CO CH₂NMe₃ 73 2bv CO CH₂NC₄H₈O 32 2bw CO CH₂NcC₄H₈ 35 2bx COCH₂NcC₅H₁₀ 35 2by CO CH₂NHCOCH₂(1-tetrazole) 14 2bz COCH₂NHCO(CH₂)₄CO₂CH₃ 62 2ca CO CH₂NHCO(CH₂)₂NHCO₂tBu 95 2cb COCH₂NHCO(CH₂)₂NH₂ 75 2cc CO CH₂NHSO₂CH₃ 29 2cd CO CH₂NHSO₂Ph 39 2ce COCH₂NHCHO 34 2cf CHOH CH₂NHCHO 124  2cg CO CONHCH₂CH₂NMe₂ 31 2ch COCONHCH₂CH₂CH₂NMe₂ 33 2ci CO CONHCH₂(4-Pyr) 13 2cj COCONHCH₂CH₂(4-imidazole) 15 2ck CO CONH(CH₂)₅NMe₂ 51 2cl COCONHCH₂(3-Pyr) 21 2cm CO CONHCH₂CH₂NC₅H₁₀ 148  2cn CO CONHCH₂CH₂NC₄H₈O26 2co CO CONH(CH₂)₂OCH₃ 18 2cp CO CONC₄H₈O 12 2cq CO CONC₄H₈NCH₃ 12 2crCO CONHCH₂(2-THF) 14 2cs CO CONHNC₄H₈NCH₃ 42 2ct CO CONMeCH₂CH₂CH₂NMe₂89 2cu CO CONMeCH₂CH₂NMe₂ 151  2cv CO CONHCH₂CH₂(2-Pyr) 18 2cw COCONMeCH₂CH₂(2-Pyr) 24 2cx CO CONMeCH₂(4-Pyr) 10 2cy COCONMeCH₂(4-Piperdinyl) 23 2cz CO CO₂CH₂CH₂NMe₂ 30 2da CO CONH(CH₂)₂OH 152db CO CONC₄H₈C(ethyleneketal) 11 2dc CO CONH[(CH₂)₂OH]₂ 18 2dd COCONC₄H₈CO 14 2de CO CH₂OEt 43 2df CO CH₂OCH₂CH₂(2-Pyr) 104  3a CO2-Aminothiazol-4-yl 25 3b CO 2-Methylthiazol-4-yl 40 3c CO2-Methyl-5-bromothiazol-4-yl 84 3d CO 2-Amino-5-methylthiazol-4-yl 50 3eCO 2-[(BOCNH)CH(CO₂tBu)(CH₂)₃NH] 46 thiazol-4-yl 3f CO2-[NH₂CH(CO₂H)(CH₂)₃NH]thiazol-4-yl 22 3g CO 2-Guanidinothiazol-4-yl 193h CO 2-(Methylamino)thiazol-4-yl 54 3i CO 2-(Acetamino)thiazol-4-yl 543j CO 2-(PhCH₂CONHCH₂)thiazol-4-yl 20 3k CO 2-(Aminomethyl)thiazol-4-yl42 31 CO 2-(Acetamino)imidazol-2-yl 47 3m CO2-(Methanesulfonylaminomethyl)thiazol-4-yl 18 3n CO2-(Acetaminomethyl)thiazol-4-yl 20 3o CO 2-(EtNHCONHCH₂)thiazol-4-yl 203p CO 2-(tBuSO₂CH₂)thiazol-4-yl 21 3q CO 2-(tBuO₂CCH₂)thiazol-4-yl 29 3rCO 2-(IsopentanoylNHCH₂)thiazol-4-yl 56 3s CO2-(PropanoylNHCH₂)thiazol-4-yl 56 3t CO 2-(IsobutanoylNHCH₂)thiazol-4-yl32 3u CO 2-(ButanoylNHCH₂)thiazol-4-yl 42 3v CO2-(PentanoylNHCH₂)thiazol-4-yl 56 3w CO 2-(CyclopropanecarbonylNHCH₂)-49 thiazol-4-yl 3x CO 2-(CyclopentanecarbonylNHCH₂)- 52 thiazol-4-yl 3yCO 2-(tButylCO₂CH₂)thiazol-4-yl 60 3z CO 2-(CH₃SO₂CH₂)thiazol-4-yl 383aa CO 2-(Oxazol-5-yl)thiazol-4-yl 66 3ab CO 2-(Glucosamino)thiazol-4-yl17 4a CO 2-(CH₃O₂C)pyrrolidine-CH₂CO 12 4b CO2-(tBuO₂C)pyrrolidine-CH₂CO 12 4c CO 2-(HO₂C)pyrrolidine-CH₂CO  7 4d COtBocNH(CH₂)₂NHCO(CH₂)₂CO 16 4e CO H₂N(CH₂)₂NHCO(CH₂)₂CO 22 4f COMorpholino-CO(CH₂)₂CO 13 4g CO HO(CH₂)₂NHCO(CH₂)₂CO  9 4h CO2-(tBuO₂C)pyrrolidin-1-yl-CO(CH₂)₂CO  7 4i CO Et₂NCO(CH₂)₂CO 12 4j CO2-(HO₂C)pyrrolidin-1-yl-CO(CH₂)₂CO  2 4k CO 3-(HO₂C)pyrazin-2-yl-CO  141 CO 6-Keto-4,5-dihydropyridazin-3-yl 17 4m CO6-Keto-1-methyl-4,5-dihydropyridazin-3-yl 12 4n CO HO₂C(CH₂)₃CO  2 4o CO2-(H₂NCO)pyrrolidin-1-yl-CO(CH₂)₂CO 13 4p CO Piperidin-1-yl-CO(CH₂)₂CO10 4q CO 4-BOC-Piperazin-1-yl-CO(CH₂)₂CO 10 4r COPiperazin-1-yl-CO(CH₂)₂CO 15 4s CO Octahydroazocin-1-yl-CO(CH₂)₂CO 26 4tCO Pyrrolidin-1-yl-CO(CH₂)₂CO 16 5a CH₂ H 108  5b CH₂ Br 30 5c CH₂ CN 185d CH₂ CH₂NH₂ 27 5e CH₂ CH₃ 800  5f CH₂ (BOC)₂Lys-NHCH₂ 670  5g CH₂Lys-NHCH₂ 80

Example 7 PARP inhibiting data for compounds 1a, 5a, and 6b-p of formulaIV wherein V is NR¹

[0962] TABLE 3 PARP No. A B E F J R¹ R² IC₅₀ (nM) 1a CO CO (CH₂)₃ H H H36 5a CH₂ CO (CH₂)₃ H H H 108 6b CO CO CH₃ CH₃ H H H 700 6e CO CO (CH₂)₃3-Br Lys H 69 6f CO CO (CH₂)₃ 3-Cl Lys H 62 6g CO CO (CH₂)₃ 3-F Lys H 486h CH₂ CO (CH₂)₃ H H CHO 3000 6i CH₂ CO (CH₂)₃ 3-Br Lys H [35% @ 3 μM]6j CH₂ CO (CH₂)₃ 3-CN Lys H 460 6k CO CO (CH₂)₃ H H CHO 78 6l CO CO(CH₂)₃ H H CH₂OH 138 6m CO CO (CH₂)₃ H CH₂— H 53 NMe₂ 6n CO— CO (CH₂)₃ HH H 60% (10 NH μM) 6o CH— CO/CH— (CH₂)₃ CO₂H H H 287 OH/ OH CO 6p CO CO(CH₂)₃ CH₂NMe₂ CH₂O H 55 H

Example 8 PARP inhibiting data for compounds 8b-j of formula IIb whereinR¹ is H, and R² is H

[0963] TABLE 4 PARP No. A B D¹ D² E,F IC₅₀ (nM) 8b CO CO CH CH (CH₂)₃ 408c CO CO Br—C CH (CH₂)₃  5 8d CO CO NC—C CH (CH₂)₃  6 8e CONH CO CU CH(CH₂)₃ 1820  8f CO CO C—Br C—Br (CH₂)₃ 20 8g CO CO C—CH₂NH₂ H (CH₂)₃ 898h CO CO CH═CH—HC═N (CH₂)₃  3 8i CO CO CH═CH—CH═N(CH₃) (CH₂)₃ 1523  8jCH₂ CH₂ HC═CH—CH═CH (CH₂)₃    42% (10 μM) 8k CO CO CH═CH—C(CH₃)═N (CH₂)₃ 2

Example 9 VEGFR2 and MLK3 inhibiting data for compounds 11a to 13b offormula IV wherein V is NR¹

[0964] Table 5 contains percent inhibition data for MLK3 and VEGFR2enzymes at the concentrations specified unless indicated otherwise. Forsome entries, an IC₅₀ value is reported. TABLE 5 MLK3 VEGFR2 No. A B E FJ R¹ R² % @ 1 μM % @ 300 mM 11a CO CH₂ (CH₂)₃ H H H 19 IC₅₀ 477(nM) 11bCO CO (CH₂)₄ H H H 26 IC₅₀ 698(nM) 11e CO CO Pr Et H H H 46 0% @ 100 nM11d CO CO (CH₂)₄ H CH₃ H 52 IC₅₀ 778(nM) 11e CO CO CH═CHCH═CH H H H 35IC₅₀ 166(nM) 11f CO CO OCH₂CH₂ H H H 62 3 11g CO CO O—CH═CH H H H 16 811h CO CO CH═CH—O H H H — — 12a CO CO CH═NCH═CH H H H 74 IC₅₀ 235(nM)12b CH₂ or CO or CH═NCH═CH H H H 34 4 CO CH₂ 12c CH₂ CO CH═NCH═CH H H H54 22 12d CO CH(OH) CH═NCH═CH H H H 5 27% @ 10 μM 12e CO CO CH═NCH═CH HCH₂CH₂CO₂Et H 20 0 12f CO CO CH═NCH═CH H CH₂CH₂CH₂— H 14 10 OH 12g CO COCH═NCH═CH H CH₂CH₂OH H 15 22 12h CO CO CH═NCH═CH H CH₂CO₂Et H 35 24 12iCO CO CH═NCH═CH H Pyrid-2-yl-CH₂ H 40 26 12j CO CO CH═NCH═CH HCH₂CH₂CO₂H H 2 18 12k CO CO CH═NCH═CH H CH₂CH₂CN H 4 9 12l CO COCH═NCH═CH H 4-HO—Bn H 26 10 12m CO CO CH═NCH═CH H 4-HO—Bn 4-HO—Bn 7 312n CO CO CH═NCH═CH 3-CH₃ H H 86 IC₅₀ 94(nM) 12o CO CO CH═NCH═CH 1-CH₃ HH 73 45 12p CO CO CH═NCH═CH 3-Br H H 72 22 12q CO CO CH═NCH═CH 3- H H 4515 (MeOCH₂C H₂O₂C) 12r CH(OH) CO CH═NCH═CH 3- H H 0 2 (MeOCH₂C H₂O₂C)12s CO CO CH═NCH═CH 3- H H 80 13 (Thiophen- 2-yl) 12t CO CO CH═NCH═CH3-(1-Me- H H 67 19 pyrrol-2-yl) 12u CO CO CH═NCH═CH 3-(Pyrid-4- H H 4716 yl) 12v CO CO CH═NCH═CH 3- H H 28 COCH₂CH₂ CO₂CH₃ 12w CO CO CH═NCH═CH3- H H 21 CH═CHCO₂ Et 12x CO CO CH═NCH═CH 3-CH═CH- H H 34 CONC₄H₈O 12yCO CO CH═NCH═CH 3- H H 26 CH═CHCO NEt₂ 12z CO CO CH═NCH═CH 3- H H 22CH═CHCO NH₂ 12aa CO CO CH═NCH═CH 3- H H 42 CH═CHCN 12ab CO CO CH═NCH═CH3- H H 15 CH═CH(3- Pyr) 12ac CO CO CH═NCH═CH 3- H H 23 CH═CH(4- Pyr) 13aCO CO CH₂NMeCH₂CH₂ H H H 19 0 13b CO CO CH₂NBnCH₂CH₂ H H H 20 1

Example 10 PARP, VEGFR2, and MLK3 inhibiting data for compounds 14 and15 of formula IV wherein J is H, and R² is H

[0965] TABLE 6 PARP MLK3 No. A B E, F V % @ 10 μM % @ 1 μM 14 CO CO(CH₂)₃ S 19 18 15 CO CO (CH₂)₃ 0 18 13

Example 10a PARP inhibiting data for compounds 14a and 14b of formula IVwherein R²is H

[0966] TABLE 7 PARP No. A B E, F J V IC₅₀ (nM) 14a CO CO (CH₂)₃ 2-OCH₃NH 224 14b CO CO (CH₂)₃ 4-OCH₃ NH  19

Example 10b PARP inhibiting data for compounds 15a-15m of formula IVwherein B is CO, V is NH, R²is H, and E-F═(CH₂)₃

[0967] TABLE 8 Example A J PARP IC₅₀ (nM) 15a CO 3-OCONC₄H₈O 35 15b CO3-OCONC₄H₈NCH₃ 51 15c CO 3-OCONH(CH₂)₂OCH₃ 40 15d CO3-OCONH(CH₂)₃(1-imidazol) 32 15e CO 3-OCONH(CH₂)₃(1-butyrolactam) 28 15fCO 3-OCONHCH₂(3-pyridyl) 34 15g CO 3-OCONH(CH₂)₂(2-pyridyl) 36 15h CO3-OCONCH₃(CH₂)₂(2-pyridyl) 39 15i CO 3-OCONCH₃[CH₂(4-pyridyl)) 30 15j CO3-OCONHCH₂(5-tetrazole) 16 15k CO 3-OCONHNC₄H₈O 20 15l CO3-OCONC₄H₈N(CH₂)₂OH 15 15m CO 3-OCONH(CH₂)₂(2-pyridyl) 31

Example 11 Synthesis of Starting Materials and Intermediates

[0968] Methods and materials employed in the synthesis of startingmaterials, intermediates, and inhibitors are as follows. Thin layerchromatography was performed on silica gel plates (MK6F 60A, size 1×3in, layer thickness 250 mm; Whatman Inc., Whatman House, UK).Preparative thin layer chromatography was performed on silica gel plates(size 20×20 in, layer thickness 1000 micron; Analtech, Newark, N.J.).Preparative column chromatography was carried out using Merck,Whitehouse Station, N.J., silica gel, 40-63 mm, 230-400 mesh. HPLC wasrun under the following conditions: 1) solvents; A=0.1% TFA in water;B=0.1% TFA in acetonitrile (10 to 100% B in 20 min or 10 to 95% B in20.5 min), 2) column; zorbax Rx-C8 (4.6 mm×15 cm),3) flow rate; 1.6mL/min. ¹H NMR spectra were recorded on a GE QE Plus instrument (300MHz) using tetramethylsilane as an internal standard. Electrospray massspectra were recorded on a VG platform II instrument (FisonsInstruments).

[0969]FIG. 1 depicts the syntheses of intermediates, precursors, andstarting materials for compounds of the present invention. The synthesisof 1a is also depicted therein.

[0970] Intermediate C was prepared in the following manner. To a cooled(−78° C.) solution of indole (A, 20 g, 171 mmol) in dry THF (80 mL) wasslowly (over 30 min) added 2.5 M nBuLi in hexanes (68.40 mL, 171 mmol).The mixture was stirred at −78° C. for another 30 min, brought to roomtemperature and stirred for 10 min and cooled back to −78° C. Carbondioxide gas was then bubbled into the reaction mixture for 15 min,followed by additional stirring of 15 min. Excess CO₂ (with someconcomitant loss of THF) was removed at room temperature from thereaction flask by applying house vacuum. Additional dry THF (25 mL) wasadded to the reaction mixture that was cooled back to −78 ° C. 1.7 Mt-BuLi (100.6 mL, 171 mmol) was slowly added to the reaction mixtureover 30 min. Stirring was continued for 2 h at −78° C., followed by slowaddition of a solution of cyclopentanone (B, 15.79 g, 188 mmol) in dryTHF (80 mL). After an additional stirring of 1 h at −78° C., thereaction mixture was quenched by dropwise addition of water (10 mL)followed by saturated NH₄Cl solution (100 mL). Ethyl ether (300 mL) wasadded to the flask and the mixture was stirred for 10 min at roomtemperature. The organic layer was separated, dried (MgSO₄),concentrated and triturated with ethyl ether (40 mL). The separatedsolid was filtered, washed with cold ether and dried under high vacuumto give 22.40 g of compound C as a white solid. Another crop of 4.88 gwas obtained from mother liquor and washings. Physical propertiesinclude mp 133-141° C.; R_(t)8.68 min; ¹H-NMR (DMSO-d₆) δ8.46 (br. s,1H), 7.58 (d, 1H), 7.36 (d, 1H), 7.17 (t, 1H), 7.09 (t, 1H), 6.34 (s,1H), 2.2-1.6 (m, 8H). An analytical sample was recrystallized fromrefluxing methanol-water. Anal. Calcd. for C₁₃H₁₅NO: C, 77.58; H, 7.51;N, 6.96. Found: C, 77.13; H, 7.12; N, 6.96.

[0971] Intermediate D was prepared in the following manner. To asolution of compound C (20 g, 99.50 mmol) in acetone (150 mL) was addedslowly 2 N HCl (20 mL) over a period of 10 min. The mixture was stirredfor another 10 min and water (300 mL) was added to it. On standing,slowly a precipitate appeared. The precipitate was filtered washed witha mixture of water-acetone (2:1, 3×50 mL) and dried under vacuum togenerate 13.57 g of D that was used in the next step without any furtherpurification. The combined mother liquor and washings, on standing,generated another 3.72 g of white solid. Physical properties for Dinclude; mp 166-167° C.;. ¹H-NMR (DMSO-d₆) δ8.12 (br. s, 1H), 7.57 (d,1H), 7.33 (d, 1H), 7.16 (t, 1H), 7.06 (t, 1H), 6.42 (s, 1H), 6.01 (s,1H), 2.79 (m, 2H), 2.60 (m, 2H), 2.08 (quintet, 2H). An analyticalsample was purified by chromatography on silica gel (hexanes-ether,80:20). Anal. Calcd for C₁₃H₁₃N: C, 85.21; H, 7.15; N, 7.64. Found: C,85.08; H, 7.16; N, 7.64.

[0972] Intermediate F was prepared in the following manner. A mixture ofcompound D (13.57 g, 74.20 mmol) and E (14.4 g, 148 mmol) was mixedthoroughly and heated neat at 190° C. in a sealed tube for 1 h, cooledto room temperature, triturated with cold methanol and filtered. Theresidue was washed several times with cold methanol and dried under highvacuum to generate 10.30 g of compound F that was used in the next stepwithout any further purification. Compound F is characterized as ayellow amorphous solid; ¹H-NMR (DMSO-d₆) δ11.15 (s, 1H), 10.89 (s, 1H),7.65 (d, 1H), 7.23 (d, 2H), 6.91 (m, 2H), 4.24 (d, 1H), 3.30 (m, 2H),2.60 (m, 1H), 2.14 (m, 1H), 1,92 (m, 1H), 1.45 (m, 3H), 1.13 (m, 1H). MSm/e 279 (M−H)⁻.

[0973] Compound G (1a,5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione)was prepared in the following manner. A mixture of compound F (10.20 g,36.42 mmol), DDQ (20.7 g, 91.18 mmol), and toluene (100 mL) was heatedat 60° C. in a sealed tube overnight, cooled to room temperature andfiltered. The filtrate was washed several times with methanol (totalvolume 250 mL) to remove all the by-products. Drying under high vacuumgenerated 7.8 g of compound G (1a) that was used without any furtherpurification. Compound G, also identified as 1a, occurs as a yellowamorphous solid showing R, 10.90 min; ¹H-NMR (DMSO-d₆) δ11.80 (s, 1H),10.90 (s, 1H), 8.70 (s, 1H), 7.50 (m, 2H), 7.20 (t, 1H), 3.25 (2 sets oft, 4H), 2.25 (broad m, 2H); MS m/e 275 (M−H).

[0974] The following examples are preparations of precursors andcompounds within the scope of the present invention.

Example 12 Preparation of 1b

[0975] To a slurry of sodium hydride (60% in oil, 0.016 g, 0.4 mmol) indry DMF (2 mL) was slowly added 1a (0.1 g, 0.36 mmol) in dry DMF (3 mL).After the evolution of H₂-gas ceased, benzyl 3-mesylpropyl ether (0.11g, 0.45 mmol) in dry DMF (1 mL) was added to the reaction flask. Themixture was stirred at 60° C. for 1.5 h, poured into ice-water (ca. 10g) and extracted into ethyl acetate (2×15 mL). The combined organiclayer was washed with water (1×10 mL), brine (1×10 mL) and concentratedto give a residue that was triturated with ether-hexane (1;1, 5 mL) togive a solid. The solid was washed with methanol and dried to give 0.046g of 1. Compound 1 is characterized as a yellow amorphous solid; R_(t)17.92 min; ¹H-NMR (DMSO-d₆) δ1.90 (s, 1H), 8.70 (d, 1H), 7.50 (m, 2H),7.25 (t, 1H), 7.10 (m, 5H), 4.30 (s, 2H), 3.70 (t, 2H), 3.50 (t, 2H),3.25 (2 sets of t, 4H), 2.25 (m, 2H), 1.80 (m, 2H); MS m/e 423 (M−H).

Example 13 Preparation of 1c.

[0976] To a slurry of sodium hydride (60% in oil, 0.016 g, 0.4 mmol) indry DMF (2 mL) was slowly added 1a (0.1 g, 0.36 mmol) in dry DMF (3 mL).After the evolution of H₂-gas ceased, benzyl 4-bromobutyronitrile (0.08g, 0.54 mmol) in dry DMF (1 mL) was added to the reaction flask. Themixture was stirred at 60° C. for 1.5 h, poured into a mixture of iceand water (ca. 10 g) and filtered. The residue was washed with methanoland dried to give 0.08 g of 1c. 1c is characterized as a yellowamorphous solid; R_(t) 14.31 min; ¹H-NMR (DMSO-d₆) δ11.90 (s, 1H), 8.70(d, 1H), 7.50 (m, 2H), 7.25 (t, 1H), 3.70 (t, 2H), 3.25 (2 sets of t,4H), 2.50 (t, 2H), 2.25 (m, 2H), 1.90 (m, 2H); MS m/e 342 (M−H).

Example 14 Preparation of 1d

[0977] To a slurry of sodium hydride (60% in oil, 0.088 g, 2.2 mmol) indry DMF (4 mL) was slowly added 1a (0.55 g, 2 mmol) in dry DMF (3 mL).After the evolution of H₂-gas ceased, 1-chloro-3-iodopropane (0.49 g,0.54 mmol) in dry DMF (3 mL) was added to the reaction flask. Themixture was stirred at 100° C. for 6 h, concentrated to a smaller volumeand poured into a mixture of ice and water (ca. 20 g) and filtered. Theresidue was washed with methanol and dried to give 0.4 g of 1d. Compound1d is characterized as a yellow amorphous solid; R_(t) 16.59 min; ¹H-NMR(DMSO-d₆) δ11.90 (s, 1H), 8.70 (d, 1H), 7.50 (m, 2H), 7.25 (t, 1H), 3.70(m, 4H), 3.25 (2 sets of t, 4H), 2.25 (m, 2H), 2.10 (m, 2H); MS m/e 351and 353 (M−H for different isotopes of chlorine).

Example 15 Preparation of 1e

[0978] A solution of 1b (0.042 g, 0.1 mmol) in DMF (10 mL) washydrogenated in a Paar apparatus in presence of Pd(OH)₂ (0.020 g) and 1drop of conc. HCl at 40 psi for 2 h. The reaction mixture was thenfiltered through a Celite® pad and concentrated to give a residue thatwas triturated with methanol to generate 0.018 g of 1e. Compound 1e ischaracterized as a yellow amorphous solid; R_(t) 12.18 min; ¹H-NMR(DMSO-d₆) δ11.90 (s, 1H), 8.70 (d, 1H), 7.50 (m, 2H), 7.25 (t, 1H), 3.70(t, 2H), 3.50 (t, 2H), 3.40 (broad, 1H), 3.25 (2 sets of t, 4H), 2.25(m, 2H), 1.80 (m, 2H); MS m/e 333 (M−H).

Example 16 Preparation of 1f

[0979] A mixture of id (0.062 g, 0.18 mmol) and piperidine (0.06 g, 0.7mmol) in ethanol (4 mL) was heated (80-85° C.) in a sealed tube for 3days. After cooling, the reaction mixture was poured over a mixture ofice and water (ca. 20 g) and filtered. The residue was dried, dissolvedin methanol (5 mL) and treated with black carbon. Filtration and solventevaporation generated 0.005 g of 1f. Compound 1f is characterized as ayellow amorphous solid; R_(t) 10.63 min; MS m/e 402 (M+H).

Example 17 Preparation of 1g

[0980] A mixture of 1d (0.066 g, 0.19 mmol) and excess morpholine inethanol (2 mL) was heated (80-85° C.) in a sealed tube for 3 days. Aftercooling, the reaction mixture was concentrated, taken into methanol (3mL) and cooled to 0° C. Dropwise addition of water to the above solutionthen generated a solid that was filtered and redissolved in ethylacetate. Drying and solvent evaporation gave 0.019 g of 1g. Compound 1gis characterized as a yellow amorphous solid; R_(t) 12.91 min; ¹H-NMR(DMSO-d₆) δ11.90 (s, 1H), 8.70 (d, 1H), 7.50 (m, 2H), 7.25 (t, 1H), 3.70(t, 2H), 3.25 (m, 6H), 2.25 (m, 10H), 1.80 (m, 2H); MS m/e 404 (M+H).

Example 18 Preparation of 1h

[0981] A mixture of 1d (0.052 g, 0.15 mmol) and excess diethylamine inethanol (2 mL) was heated (80-85° C.) in a sealed tube for 3 days. Aftercooling, the reaction mixture was poured over a mixture of ice and water(ca. 20 g) and filtered. The residue was washed several times with waterand dried under high vacuum to generate 0.015 g of 1h. Combined motherliquor and washings, on standing, produced another 0.014 g of 1h.Compound 1h is characterized as a yellow amorphous solid; R_(t) 10.47min; ¹H-NMR (CDCl₃) δ9.00 (d, 1H), 8.30 (s, 1H), 7.50 (m, 2H), 7.25 (t,1H), 3.70 (t, 2H), 3.30 (t, 2H), 3.10 (t, 2H), 2.25 (m, 6H), 2.30 (m,2H), 1.90 (m, 2H), 1.00 (t, 6H); MS m/e 390 (M+H).

Example 19 Preparation of 1j

[0982] To a slurry of sodium hydride (60% in oil, 0.008 g, 0.2 mmol) indry DMF (1 mL) was slowly added 1a (0.05 g, 0.18 mmol) in dry DMF (2mL). After the evolution of H₂-gas ceased, phenylsulfonyl chloride(0.035 g, 0.2 mmol) in dry DMF (3 mL) was added to the reaction flask.The mixture was stirred at 60° C. for 1 h, poured into ice-water (ca. 20g) and filtered. The residue was successively washed with water andmethanol and dried to give 0.036 g of 1j. Compound 1j is characterizedas a yellow amorphous solid; R_(t) 16.19 min; ¹H-NMR (DMSO-d₆) δ12.10(s, 1H), 8.70 (d, 1H), 8.10 (d, 2H), 7.70 (m, 3H), 7.50 (m, 2H), 7.30(t, 1H), 3.25 (2 sets of t, 4H), 2.25 (m, 2H); MS m/e 415 (M−H).

Example 20 Preparation of 1k

[0983] To a slurry of sodium hydride (60% in oil, 0.048 g, 1.2 mmol) indry DMF (2 mL) was slowly added 1a (0.3 g, 1.1 mmol) in dry DMF (4 mL)and the mixture was stirred for 30 min. In a separate flask, a mixtureof Boc-Lys(Boc) dicyclohexylamine salt (1.16 mmol, 2.2 mmol), TBTU (0.71g, 2.2 mmol), NMM (0.22 g, 2.2 mmol) in dry DMF (5 mL) was stirred for30 min and added to the first reaction-flask. The mixture was stirredfor 1 h (HPLC showed 70% of a new product), poured into a mixture of iceand water (ca. 20 g) and filtered. The residue was washed several timeswith water, dried under high vacuum, dissolved in dioxane (3 mL) and toit added 4 N HCl in dioxane (3 mL). After stirring for 1 h at roomtemperature, the reaction mixture was filtered and the residue waswashed several times with dioxane, followed by ether.

[0984] Drying under high vacuum generated 0.1 g of 1k. Compound 1k ischaracterized as a yellow amorphous solid; R_(t) 5.93 min; ¹H-NMR(DMSO-d₆) δ12.20 (s, 1H), 8.80 (d, 1H), 8.70 (broad, 3H), 8.00 (broad,3H), 7.60 (m, 2H), 7.30 (t, 1H), 5.00 (broad, 1H), 3.25 (m, 4H), 2.70(broad, 2H), 2.25 (m, 2H), 2.00 (2 sets of broad, 2H), 1.50 (broad m,4H); MS m/e 406 (M+2H).

Example 21 Preparation of 1l

[0985] This compound was prepared following the same procedure asdescribed before for the synthesis of 1k. Thus, starting from 0.1 g of1a and 0.14 g of Boc-beta-alanine, 0.025 g of 1l was obtained. 1l ischaracterized as a yellow amorphous solid; R_(t) 7.45 min; ¹H-NMR(DMSO-d₆) δ12.20 (s, 1H), 8.70 (d, 1H), 8.00 (broad, 3H), 7.50 (m, 2H),7.25 (t, 1H), 3.30 (t, 2H), 3.25 (m, 6H), 2.25 (m, 2H); MS m/e 348(M+H).

Example 22 Preparation of 1m

[0986] This compound was prepared following the same procedure asdescribed before for the synthesis of 1k. Thus, starting from 0.1 g of1a and 0.13 g of Boc-glysine, 0.028 g of 1m was obtained. Compound 1m ischaracterized as a yellow amorphous solid; R_(t) 7.14 min; ¹H-NMR(DMSO-d₆) δ12.20 (s, 1H), 8.70 (d, 1H), 8.30 (broad, 3H), 7.60 (m, 2H),7.30 (t, 1H), 4.30 (s, 2H), 3.25 (m, 4H), 2.25 (m, 2H); MS m/e 334(M+H).

Example 23 Preparation of 1p

[0987] To a slurry of sodium hydride (60% in oil, 0.08 g, 2 mmol) in dryDMF (2 mL) was slowly added 1a (0.5 g, 1.8 mmol) in dry DMF (4 mL).After the evolution of H₂-gas ceased, benzyl 2-bromoacetate (0.46 g, 2mmol) in dry DMF (2 mL) was added to the reaction flask. The mixture wasstirred at 60° C. for 1 h, poured into a mixture of ice and water (ca.20 g) and filtered. The crude residue was then purified by flash columnchromatography (20% THF in toluene) to generate 0.2 g of 1p. Compound 1pis characterized as a yellow amorphous solid; R_(t) 14.59 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 8.50 (d, 1H), 7.50 (m, 2H), 7.25 (m, 6H), 5.10(s, 2H), 4.50 (s, 2H), 3.25 (m, 4H), 2.25 (m, 2H); MS m/e 423 (M−H).

Example 24 Preparation of 1n

[0988] To a slurry of sodium hydride (60% in oil, 0.029 g, 0.73 mmol) indry DMF (2 mL) was slowly added 1a (0.17 g, 0.6 mmol) in dry DMF (3 mL).After the evolution of H₂-gas ceased, benzyl 2-bromoethyl ether (0.16 g,0.73 mmol) in dry DMF (1 mL) was added to the reaction flask. Themixture was stirred at 60° C. for 4 h, poured into a mixture of ice andwater (ca. 10 g) and filtered. The crude residue was then purified byflash column chromatography (20% THF in toluene) to generate 0.13 g ofin. Compound 1n is characterized as a yellow amorphous solid; R_(t)14.62 min; ¹H-NMR (DMSO-d₆) δ11.90 (s, 1H), 8.50 (d, 1H), 7.50 (m, 2H),7.20 (m, 6H), 4.50 (s, 2H), 3.70 (overlapping dd, 2H), 3.60 (overlappingdd, 2H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H); MS m/e 409 (M−H).

Example 25 Preparation of 1o

[0989] A solution of 1n (0.1 g, 0.24 mmol) in DMF (8 mL) washydrogenated in a Paar apparatus in presence of Pd(OH)₂ (0.025 g) and 1drop of conc. HCl at 45 psi for 16 h. The reaction mixture was thenfiltered through a Celite® pad and concentrated to give 0.077 g of thecorresponding debenzylated product as a yellow amorphous solid; R_(t)10.37 min; ¹H-NMR (DMSO-d₆) d 11.90 (s, 1H), 8.75 (d, 1H), 7.50 (m, 2H),7.25 (t, 1H), 4.80 (t, 1H), 3.60 (m, 4H), 3.25 (2 sets oft, 4H), 2.25(m, 2H). MS m/e 319 (M−H).

[0990] The above product (0.052 g, 0.163 mmol) was converted, in thepresence of p-toluenesulfonyl chloride (0.214 g, 1.122 mol) and pyridine(3 mL) to corresponding p-toluenesulfonyl derivative (0.07 g). Asolution of this compound (0.05 g) in THF (2 mL) and excess diethylaminewas then refluxed in a sealed tube for 2 days. Excess solvent andreagent were removed. The residue was washed several times with methanoland dried under high vacuum to generate 0.20 g of 1o. Compound 1o ischaracterized as a yellow amorphous solid; R_(t) 9.06 min; ¹H-NMR(DMSO-d₆) δ11.90 (s, 1H), 8.75 (d, 1H), 7.50 (m, 2H), 7.25 (t, 1H), 3.60(t, 2H), 3.25 (2 sets oft, 4H), 2.60 (t, 2H), 2.50 (q, 4H), 2.25 (m,2H), 0.80 (t, 6H); MS m/e 376 (M+H).

Example 26 Preparation of 1q

[0991] A solution of 1p (0.030 g, 0.071 mmol) in MeOH-DMF (1:1, 10 mL)was hydrogenated in a Paar apparatus in presence of 10% Pd—C (DeGussatype, 50% water content) at 40 psi for 15 min. The reaction mixture wasthen filtered through a Celite® pad and concentrated to give 0.025 g of1p. Compound 1p is characterized as a yellow amorphous solid; R_(t)10.36 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 8.75 (d, 1H), 7.50 (m, 2H),7.25 (t, 1H), 4.25 (s, 2H), 4.00-3.00 (broad, 1H), 3.25 (m, 4H), 2.25(m, 2H); MS m/e 333 (M−H).

Example 27 Preparation of 1r

[0992] To a solution of 1q (0.20 g, 0.060 mmol) in dry DMF (2 mL) at 0°C. was added EDCI (0.012 g, 0.063 mmol). The mixture was stirred for 10min and to it added HOBt-ammonia complex (0.017 g, 0.112 mmol; 1.12 g ofthe complex was prepared by reacting 1.30 g of HOBt and 1.1 mL of 28%ammonium hydroxide in 10 mL of acetone, followed by removal of thesolvents). The ice-bath was removed and the mixture was stirredovernight. It was then poured into a mixture of ice and water (ca. 10 g)and filtered. The residue was washed several times with water and driedunder high vacuum to generate 0.012 g of 1r. Compound 1r ischaracterized as a yellow solid; R_(t) 9.28 min; MS m/e 332 (M−H).

Example 28 Preparation of 1s

[0993] To a slurry of sodium hydride (60% in oil, 0.016 g, 0.4 mmol) indry DMF (2 mL) was slowly added la (0.1 g, 0.36 mmol) in dry DMF (3 mL).After the evolution of H₂-gas ceased, N-bromomethylphthalimide (0.096 g,0.4 mmol) in dry DMF (1 mL) was added to the reaction flask. The mixturewas stirred at 60° C. for overnight, poured into a mixture of ice andwater (ca. 10 g) and filtered. The residue was washed several times withwater and dried under high vacuum to generate 0.1 g of is. 1s ischaracterized as a yellow solid; R_(t) 13.07 min ¹H-NMR (DMSO-d₆) δ12.00(s, 1H), 8.75 (d, 1H), 7.80 (m, 4H), 7.50 (m, 2H), 7.25 (t, 1H), 5.50(s, 2H), 3.25 (m, 4H), 2.25 (m, 2H); MS m/e 434 (M−H).

Example 29 Preparation of 1t11-Methyl-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[0994] Compound 5a (20 mg, 0.076 mmol) in DMF (0.2 mL) was treated withMeI (11.4 mg, 0.08 mmol) and NaH (8.1 mg of 60%, 0.2 mmol) for 18 h.Water (1 mL) was added. The resulting precipitate was refluxed withacetone, cooled, and the precipitate was collected to afford the productas an off-white solid (9 mg, 43% yield). MS m/e 277 (M+H)⁺. NMR(DMSO-d₆) δ8.45 (s, 1H), 7.95 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.30(t, 1H), 4.82 (s, 2H), 4.12 (s, 3H), 3.52 (t, 2H), 3.40 (t, 2H), 2.25(quintet, 2H).

Example 30 Preparation of 1u11-[Bis(t-butoxycarbonyl)-L-lysyl]-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolot3,4-c]carbazole-7(6H)-one

[0995] The bis(t-butoxycarbonyl)-lysyl derivative was prepared asdescribed for 1k, and purified by chromatography (CH₂Cl₂-Et₂O) to give ayellow glass. MS m/e 613 (M+Na)⁺.

Example 31 Preparation of 1v11-L-Lysyl-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-onedihydrochloride

[0996] The BOC groups of 1u were hydrolyzed with 2M HCl in dioxane toafford the product as a tan solid. MS m/e 391 (M+H)⁺, 263 (M+H-Lysyl)⁺.NMR (DMSO-d₆) δ12.1 (s, 1H), 8.6 (s, 3H), 8.4 (s, 3H), 8.08 (1H, d), 8.0(s, 3H), 7.62 (d, 1H), 7.50 (t, 1H), 7.32 (t, 1H), 5.35 (s, 2H), 5.15(m, 1H), 3.85 (m, 1H), 2.75 (m, 2H), 2.2-1.5 (m, 6H).

Example 32 Preparation of 2a

[0997] A mixture of 1a (1 g, 3.6 mmol), N-bromosuccinimide (0.64 g, 3.62mmol) and dry DMF (20 mL) was stirred at room temperature for 1 h. Thereaction mixture was then poured into methanol (100 mL) and filtered.The precipitated solid was washed several times with methanol and driedunder high vacuum to generate 0.97 g of 2a. The product is characterizedas a yellow amorphous solid with properties; R_(t) 12.39 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 8.70 (s, 1H), 7.60 (d, 1H),7.50 (d, 1H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H); MS m/e 353 and355 (M−H for different isotopes of bromine).

Example 33 Preparation of 2b

[0998] A mixture of 1a (0.20 g, 0.72 mmol), N-chlorosuccinimide (0.106g, 0.75 mmol) and dry DMF (5 mL) was heated in a sealed tube at 60° C.for 1 h. After cooling, the reaction mixture was poured into methanol(10 mL) and filtered. The precipitated solid was washed several timeswith methanol and dried under high vacuum to generate 0.11 g of 2b.Compound 2b is a yellow amorphous solid; R_(t) 14.06 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 8.70 (s, 1H), 7.50 (m, 2H),3.25 (2 sets of t, 4H), 2.25 (broad m, 2H); MS m/e 309 and 301 (M−H fordifferent isotopes of chlorine).

Example 34 Preparation of 2c

[0999] Starting with 5-fluoroindole, this compound was preparedfollowing the same multistep procedure as described for the synthesis of1a from indole. The compound 2c is characterized as an orange amorphoussolid; R_(t) 11.50 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H),8.50 (d, 1H), 7.50 (m, 1H), 7.30 (t, 1H), 3.25 (2 sets of t, 4H), 2.25(broad m, 2H). MS m/e 293 (M−H).

Example 35 Preparation of 2d

[1000] To a suspension of AlCl₃ (0.072 g, 0.54 mmol) in1,2-dichloroethane (2 mL) at 0° C. was added acetyl chloride (0.042 g,0.54 mmol). A suspension of 1a (0.050 g, 0.18 mmol) in1,2-dichloroethane (4 mL) was slowly added to the reaction flask. Thecooling bath was removed and the mixture was stirred for 4 h, pouredover a mixture of ice (ca. 10 g) and 2 N HCl (10 mL) and filtered. Theresidue was washed with water, stirred overnight in a mixture ofmethanol-water (4:1, 5 mL) and filtered. It was washed with smallvolumes of methanol and ether, respectively and dried under vacuum togenerate 0.023 g of 2d. Compound 2d is characterized as a yellowamorphous solid; R_(t) 9.82 min (broad); ¹H-NMR (DMSO-d₆) δ12.25 (s,1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.00 (d, 1H), 7.50 (d, 1H), 3.25 (2sets of t, 4H), 2.70 (s, 3H), 2.25 (broad m, 2H); MS m/e 317 (M−H).

Example 36 Preparation of 2e

[1001] This compound was prepared following the same procedure asdescribed before for the synthesis of 2d. Thus, starting from 0.050 g of1a and 0.10 g of bromoacetyl bromide, 0.045 g of 2e was obtained. 2e ischaracterized as a yellow amorphous solid; R_(t) 10.76 min; ¹H-NMR(DMSO-d₆) δ12.30 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H),7.60 (d, 1H), 4.80 (s, 2H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H).MS m/e 396 (M−H).

Example 37 Preparation of 2f

[1002] This compound was prepared following the same procedure asdescribed before for the synthesis of 2e. Based on 0.2 g of 1a startingmaterial, 0.2 g of 2f was obtained. The compound 2f is characterized asa yellow amorphous solid; R_(t) 11.96 min; ¹H-NMR (DMSO-d₆) δ12.20 (s,1H), 11.00 (s, 1H), 9.50 (s, 1H), 8.20 (d, 1H), 7.50 (d, 1H), 5.70 (q,1H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H), 1.80 (d, 3H). MS m/e410 (M−H).

Example 38 Preparation of 2 g

[1003] A mixture of 2e (0.036 g, 0.09 mmol), triethylamine (0.010 g, 0.10 mmol) and N-methylpiperizine (0.010 g, 0. 10 mmol) in dry DMF (2 mL)was stirred at room temperature for 0. 5 h, poured into a mixture of iceand water (ca. 10 g) and filtered. The residue was washed several timeswith water and dried under high vacuum to generate 0.010 g of 2g.Compound 2g is characterized as a yellow amorphous solid; R_(t) 5.77min; ¹H-NMR (DMSO-d₆) δ12.25 (s, 111), 11.00 (s, 1H), 9.50 (s, 1H), 8.20(d, 1H), 7.50 (d, 1H), 3.70 (s, 2H), 3.25 (2 sets of t, 4H), 2.50(broad, 4H), 2.25 (broad m, 6H), 2.10 (t, 3H). MS m/e 417 (M+H).

Example 39 Preparation of 2h

[1004] A mixture of 2e (0.040 g, 0.10 mmol), triethylamine (0.011 g,0.11 mmol) and morpholine (0.0096 g, 0.11 mmol) in dry DMF (2 mL) wasstirred at room temperature for 1 h, poured into a mixture of ice andwater (ca. 10 g) and filtered. The residue was washed several times withwater and dried under high vacuum to generate 0.019 g of 2h. Compound 2his characterized as a yellow amorphous solid; R_(t) 6.50 min; ¹H-NMR(DMSO-d₆) δ12.25 (s, 1H), 1 1.00 (s, 1H), 9.50 (s, 1H), 8.20 (d, 1H),7.60 (d, 1H), 3.70 (s, 2H), 3.50 (broad, 4H), 3.25 (2 sets of t, 4H),2.40 (broad, 4H), 2.25 (broad m, 2H); MS m/e 404 (M+H).

Example 40 Preparation of 2i

[1005] A mixture of 2e (0.040 g, 0.1 mmol), triethylamine (0.011 g, 0.11mmol) and piperidine (0.009 g, 0.11 mmol) in dry DMF (3 mL) was stirredat room temperature for 0.5 h, poured into a mixture of ice and water(ca. 10 g) and filtered. The residue was washed several times with waterand dried under high vacuum to generate 0.034 g of 2i. Compound 2i ischaracterized as a yellow amorphous solid; R_(t) 7.32 min; ¹H-NMR(DMSO-d₆) δ12.25 (broad, 1H), 11.00 (broad, 1H), 9.50 (s, 1H), 8.20 (d,1H), 7.50 (d, 1H), 3.50 (s, 2H), 3.25 (2 sets of t, 4H), 2.40 (broad,4H), 2.25 (broad m, 2H), 1.50 (broad, 4H), 1.30 (broad, 2H). MS m/e 402(M+H).

Example 41 Preparation of 2j

[1006] A mixture of 2e (0.040 g, 0.1 mmol), triethylamine (0.012 g, 0.12mmol) and diethylamine (0.009 g, 0.12 mmol) in dry DMF (3 mL) wasstirred at room temperature for 1 h, poured into a mixture of ice andwater (ca. 10 g) and filtered. The residue was washed several times withwater and dried under high vacuum to generate 0.026 g of 2j. Compound 2jis characterized as a dark brown amorphous solid; R_(t) 7.04 min; ¹H-NMR(DMSO-d₆) δ12.25 (broad, 1H), 11.00 (broad, 1H), 9.50 (s, 1H), 8.20 (d,1H), 7.50 (d, 1H), 3.70 (s, 2H), 3.25 (2 sets of t, 4H), 2.60 (q, 4H),2.25 (broad m, 2H), 1.00 (t, 6H).

[1007] MS m/e 390 (M+H).

Example 42 Preparation of 2k

[1008] A mixture of 2e (0.050 g, 0.13 mmol), triethylamine (0.028 g,0.27 mmol) and sarcosine t-butyl ester hydrochloride (0.025 g, 0.135mmol) in dry DMF (3 mL) was stirred at room temperature for 72 h, pouredinto a mixture of ice and water (ca. 10 g) and filtered. The residue waswashed several times with water and dried under high vacuum to generate0.035 g of 2k. Compound 2k is characterized as a yellow amorphous solid;R_(t) 9.20 min (broad); ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H),9.40 (s, 1H), 8.20 (d, 1H), 7.60 (d, 1H), 4.10 (s, 2H), 3.40 (s, 2H),3.25 (2 sets of t, 4H), 2.40 (s, 3H), 2.25 (broad m, 2H), 1.40 (s, 9H);MS m/e 461 (M+H).

Example 43 Preparation of 2l

[1009] A mixture of compound 2k (0.018 g, 0.039 mmol) andtrifluoroacetic acid (0.3 mL) was stirred overnight at room temperature.Excess trifluoroacetic acid was removed and ethyl acetate (5 mL) wasadded to the reaction flask. Slowly a solid appeared that was filtered,washed several times with ethyl acetate and dried under high vacuum togenerate 0.016 g of 2l. Compound 2l is characterized as a yellowamorphous solid; R₅ 6.34 min (broad); ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H),11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H), 7.60 (d, 1H), 4.70 (s, 2H),3.70 (s, 2H), 3.50 (broad, 2H), 3.25 (2 sets of t, 4H), 2.70 (s, 3H),2.25 (broad m, 2H); MS m/e 406 (M+H).

Example 44 Preparation of 2m

[1010] To a suspension of AlCl₃ (2.89 g, 21.7 mmol) in1,2-dichloroethane (5 mL) at 0° C. was added succinic anhydride (1.086g, 10.86 mmol) in 1,2-dichloroethane (5 mL). A suspension of 1a (1 g,3.62 mmol) in 1,2-dichloroethane (10 mL) was slowly added to thereaction flask. The cooling bath was removed and the mixture was stirredfor 5 h, poured over a mixture of ice (ca. 10 g) and 2 N HCl (10 mL) andfiltered. The residue was washed with water, stirred overnight in amixture of methanol-water (4: 1, 10 mL) and filtered. The product waswashed with small volumes of water and ether, sequentially, and driedunder vacuum to generate 1.16 g of 2m. The compound 2m is characterizedas a yellow amorphous solid; R⁵ 9.17 min; ¹H-NMR (DMSO-d₆) δ12.30 (s,1H), 12.10 (broad, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.00 (d, 1H), 7.50(d, 1H), 3.40 (m, 2H), 3.25 (2 sets of t, 4H), 2.60 (m, 2H), 2.25 (broadm, 2H). MS m/e 375 (M−H).

Example 45 Preparation of 2n

[1011] To a solution of compound 2e (0.040 g, 0.1 mmol) in dry DMF (2mL) was added 1,2,4-triazole, sodium derivative (0.014 g, 0.14 mmol).The mixture was stirred for 30 min at room temperature, poured into amixture of ice and water (ca. 10 g) and filtered. The residue was washedseveral times with water and dried under high vacuum to generate 0.024 gof 2n. Compound 2n is characterized as a yellow amorphous solid; R_(t)9.28 min; ¹H-NMR (DMSO-d₆) δ12.50 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H),8.50 (s, 1H), 8.20 (d, 1H), 8.00 (s, 1H), 7.50 (d, 1H), 6.00 (s, 2H),3.25 (2 sets of t, 4H), 2.25 (broad m, 2H); MS m/e 386 (M+H).

Example 46 Preparation of 2o

[1012] CuCN method: A mixture of 2a (0.1 g, 0.28 mmol), CuCN (0.075 g,0.85 mmol) and 1-methyl-2-pyrrolidinone (4 mL) was heated at 175° C. ina sealed tube overnight, cooled to room temperature, passed through asilica pad, concentrated to a small volume and poured into water (20mL). The precipitated solid was filtered, washed with water, dried andpurified by column chromatography (eluant: EtOAc) to generate 0.006 g of2o.

[1013] Zn(CN)₂ method: A mixture of 2a (2.33 g, 6.56 mmol) and Zn(CN)₂(1.56 g, 13.3 mmol) were dissolved in DMF (22 mL) under nitrogen.Pd(Ph₃P)₄ (1.17 g, 0.10 mmol, 15 mol%) was added, and the mixture wasstirred at 125° C. for 80 min. The warm solution was vacuum filteredthrough Celite® and the pad rinsed with hot DMF. The filtrate wasdiluted with two volumes of water. The resulting precipitate wascollected, dried, and triturated with ethyl acetate and rinsed withethyl acetate, then ether, affording the slightly impure product as abrownish-orange solid (2.17 g). This could be purified by columnchromatography as above. Compound 2o is characterized as a yellowamorphous solid; R_(t) 10.51 min; ¹H-NMR (DMSO-d₆) δ12.40 (s, 1H), 11.00(s, 1H), 9.00 (s, 1H), 7.80 (d, 1H), 7.60 (d, 1H), 3.25 (2 sets of t,4H), 2.25 (broad m, 2H);

[1014] MS m/e 300 (M−H).

Example 47 Preparation of 2p3-(Aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dionehydrochloride

[1015]3-Cyano-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione2o (580 mg) was dissolved in DMF (58 mL). The solution was saturatedwith ammonia and hydrogenated at 55 psi over freshly prepared (R.Mozingo, Org. Synth. 1955 3, 181-183) W-2 Raney nickel (2.4 g) for 7days. Additional Raney nickel was added as required. The precipitate,containing catalyst and some product, was removed and the solventevaporated from the filtrate to afford the orange crude product (408mg). The crude product was suspended in water (70 mL) and IM HCl (1.5mL) and mixed with Celite® 521 then filtered. The residue waslyophilized to give the product as a yellow solid (288 mg, 44% yield).NMR (DMSO-d₆) δ12.20 (s, 1H), 11.02 (s, 1H), 8.85 (s, 1H), 8.36 (br. s,3H), 7.65 (m, 2H), 4.19 (br. s, 2H), 4.00 (s, 2H), 3.28 (t, 2H), 3.21(t, 2H), 2.31 (quintet, 2H). NMR (D₂0) d 7.58 (s, 1H), 7.24 (d, 1H),7.03 (d, 1H). 4.07 (s, 2H), 2.10 (m, 2H), 1.90 (m, 2H), 1.65 (m, 2H). MSm/e 289 (M+H−NH₃)⁺, 306 (M+H)⁺. Anal. Calcd for C₁₈H₁₅N₃O₂-2.1 HCl-1.6H₂O: C, 52.64; H, 4.98; N, 10.23. Cl, 18.13. Found: C, 52.38; H, 4.61;N, 10.03; Cl, 18.29.

Example 48 Preparation of 2qBis-[5(6H),7-dioxo-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazol-3-ylmethyl]aminehydrochloride

[1016] When 3-cyano-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione 2o (115mg) dissolved in DMF was hydrogenated as above but in the absence ofammonia, HPLC indicated a 60:40 mixture of dimer 2q and monomer 2p. Themixture was stirred with 0.01 M HCl (50 mL) and filtered. Theprecipitate was extracted with DMF (15 mL) to give the product as ayellow solid. NMR (DMSO-d₆) δ10.09 (s, 2H), 9.31 (s, 2H), 8.03 (d, 2H),7.73 (d, 2H), 4.13 (br. s, 4H), 3.28 (t, 4H), 3.21 (t, 4H), 2.30(quintet, 4H). MS m/e 594 (M+H)⁺.

Example 49 Preparation of 2r 3-(Acetylaminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[alpyrrolo[3,4-c]carbazole-5(6H),7-dione.

[1017] EDCI (30 mg, 0.156 mmol) was added to a suspension of3-(aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dionehydrochloride (2p, 31 mg, 0.10 mmol), NMM (15 uL, 13 mmol), HOBT-H₂O (16mg, 0.10 mmol), and acetic acid (10 mg, 0.17 mmol) in DMF (0.5 mL). Allsolids dissolved 10 min. After 2 days, water (4 mL) was added. Theprecipitate was collected and rinsed with water, saturated NaHCO₃,water, 1 M HCl, and water, then dried to afford the product (2r, 23 mg,73% yield) as a golden-brown solid. NMR (DMSO-d₆) δ11.92 (s, 1H), 10.95(s, 1H), 8.71 (s, 1H), 8.43 (t, 1), 7.54 (d, 1H), 7.43 (d, 1H), 4.43 (d,2H), 3.27 (t, 2H), 3.19 (t, 2H), 2.30 (quintet, 2H), 1.91 (s, 3H). MSm/e 346 (M−H)⁻.

Example 50 Preparation of 2s3-(Propanoylaminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1018] Prepared from 2p and propionic acid by a similar procedure tothat used in the preparation of 2r. NMR (DMSO-d₆) δ11.93 (s, 1H), 10.96(s, 1H), 8.71 (s, 1H), 8.40 (t, 1), 7.52 (d, 1H), 7.44 (d, 1H), 4.42 (d,2H), 3.30 (t, 2H), 3.22 (t, 2H), 2.35 (quintet, 2H), 2.22 (q, 2H), 1.11(t, 3H). MS m/e 360 (M−H)⁻.

Example 51 Preparation of 2t3-(Butanoylaminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1019] Prepared from 2p and butyric acid by a procedure analogous forthe preparation of 2r. NMR (DMSO-d₆) δ11.90 (s, 1H), 10.96 (s, 1H), 8.70(s, 1H), 8.40 (t, 1), 7.52 (d, 1H), 7.42 (d, 1H), 4.42 (d, 2H), 3.35 (t,2H), 3.26 (t, 2H), 2.28 (quintet, 2H), 2.15 (t, 2H), 1.60 (m, 2H), 0.89(t, 3H). MS m/e 374 (M−H)⁻.

Example 52 Preparation of 2u3-(Benzoylaminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1020] Prepared from 2p and benzoic acid by a similar procedure to thatdescribed for the preparation of 2r. NMR (DMSO-d₆) δ11.94 (s, 1H), 10.95(s, 1H), 9.18 (t, 1H), 9.82 (s, 1H), 7.95 (d, 1H), 7.50 (m, 6H), 4;67(d, 2H), 3.27 (t, 2H), 3.19 (t, 2H), 2.30 (quintet, 2H). MS m/e 408(M−H)⁻.

Example 53 Preparation of 2v3-(N-(2-(N-Boc-amino)acetyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1021] Prepared from 2p and BOC-glycine by a similar procedure to thatdescribed for the preparation of 2r. NMR (DMSO-d₆) δ11.93 (s, 1H), 10.96(s, 1H), 8.71 (s, 1H), 8.38 (t, 1), 7.54 (d, 1H), 7.46 (d, 1H), 6.96(br. s, 1H), 4.45 (d, 2H), 3.61 (d, 2H), 3.27 (t, 2H), 3.19 (t, 2H),2.33 (quintet, 2H), 1.40 (s, 9H). MS m/e 461 (M−H)⁻.

Example 54 Preparation of 2w3-(N-(4-(N-Boc-amino)butanoyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1022] Prepared from 2p and BOC-4-aminobutyric acid by a similarprocedure to that described for 2r. NMR (DMSO-d₆) δ11.87 (s, 1H), 10.90(s, 1H), 8.70 (s, 1H), 8.36 (t, 1), 7.52 (d, 1H), 7.43 (d, 1H), 6.77(br. s, 1H), 4.41 (d, 2H), 3.24 (t, 2H), 3.17 (t, 2H), 2.93 (q, 2H),2.29 (quintet, 2H), 2.15 (t, 2H), 1.65 (quintet, 2H), 1.37 (s, 9H). MSm/e 489 (M−H)⁻.

Example 55 Preparation of 2x3-(N-(2-(Amino)acetyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1023] This compound was prepared by treatment of 2v with 2 M HCl indioxane. NMR (D₂O) δ7.40 (s, 1H), 7.07 (d, 1H), 6.89 (d, 1H), 4.32 (br.s, 2H), 3.90 (br. s, 2H), 3.76 (m, 4H), 1.99 (m, 4H), 1.65 (m, 2H). MSm/e 363 (M+H)⁺.

Example 56 Preparation of 2y3-(N-(4-(Amino)butanoyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1024] This compound was prepared by treatment of 2w with 2 M HCl indioxane. NMR (D₂O) δ7.36 (s, 1H), 7.03 (d, 1), 6.85 (d, 1H), 4.26 (s,2H), 3.84 (t, 2H), 3.76 (m, 2H), 3.68 (t, 2H), 3.09 (t, 2H), 2.45 (t,2H), 2.02 (m, 4H). 2.15 (t, 2H), 1.61 (m, 2H). MS m/e 391 (M+H)⁺.

Example 57 Preparation of 2z3-(N-(3-(Methoxycarbonyl)propanoyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1025] Prepared from 2p and monomethyl succinate by a similar procedureto that described for the preparation of 2r. MS m/e 418 (M−H)⁻.

Example 58 Preparation of 2aa3-(N-(4-(Methoxycarbonyl)butanoyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1026] Prepared from 2p and monomethyl glutarate by a similar procedureto that described for the preparation of 2r. MS m/e 432 (M−H)⁻.

Example 59 Preparation of 2ab3-(N-(3-(Carboxy)propanoyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]-pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1027] Succinic anhydride (3.1 mg, 0.031 mmol) was added to a suspensionof3-(aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dionehydrochloride (9.8 mg, 0.029 mmol) and NMM (9 uL, 0.082 mmol) in DMF(0.2 mL). The solid dissolved within 30 min, and then a new precipitateformed. After 1 h, 1 M HCl was added. The precipitate was collected,rinsed with water, and then dried to afford the product 2ab (11.4 mg,98% yield) as a yellow solid. MS m/e 404 (M−H)⁻.

Example 60 Preparation of 2ac3-(N-(4-(Carboxy)butanoyl)aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]-pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1028] Prepared from glutaric anhydride by a similar procedure asdescribed for 2ab. MS m/e 418 (M−H)⁻.

Example 61 Preparation of 2ad3-(N-Boc-aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dione

[1029] NMM (14 mg, 0.14 mmol) was added to a mixture of3-(aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H),7-dionehydrochloride (2p, 15 mg, 0.045 mmol) and di-t-butyl dicarbonate (18 mg,0.082 mmol) in DMF (1 mL). After 2 hr, the mixture was filtered, andwater (5 mL) was added. The precipitate was collected and rinsed with 3%citric acid, saturated NaHCO₃, and water, then dried to afford theproduct (12 mg, 67% yield) as a golden-brown solid. This solid could bepurified by chromatography on silica gel (EtOAc) to give a yellow solid.NMR (CDCl₃) δ8.78 (s, 1H), 8.34 (s, 1H), 7.49 (m, 1H), 7.31 (m, 1H),5.00 (m, 1H), 4.51 (s, 1H), 3.40 (t, 2H), 3.16 (t, 2H), 2.39 (quintet,2H), 1.53 (s, 9H). MS m/e 404 (M−H)⁻.

Example 62 Preparation of 2ae

[1030] To a suspension of 5a (0.1 g, 0.36 mmol) in methylene chloride (2mL) at 0° C., was slowly added chlorosulfonic acid (0.05 g, 0.4 mmol).The reaction mixture was stirred at 0° C. for another 30 min, thenstirred at room temperature overnight and filtered. The residue waswashed successively with methylene chloride and ether. It was thenpurified by preparative HPLC to generate 0.008 g of 2ae. Compound 2ae isa yellow amorphous solid; R^(t) 4.89 min (broad); ¹H-NMR (DMSO-d₆)δ12.00 (s, 1H), 11.00 (s, 1H), 9.10 (s, 1H), 7.75 (d, 1H), 7.40 (d, 1H),3.25 (2 sets oft, 4H), 2.50 (s, 1H), 2.25 (broad m, 2H); MS m/e 355(M−H).

Example 62a Preparation of 2af

[1031] To a solution of example 5a (26 mg, 0.10 mmol) in DMF (2 ml) wasadded N-chlorosuccinimide (15 mg, 0.11 mmol). The mixture was stirred atroom temperature for 18 h before being added dropwise to a stirred flaskof water (10 ml). The resulting precipitate was collected by suctionfiltration, washed with water (3×5 ml) and dried to constant weight togive 15 mg (52%) of the title compound as an off-white solid. MS:m/e=295/297 (M+H)⁺.

Example 62b Preparation of 2ag

[1032] A slurry of example 5c (305 mg, 1.06 mmol) in 1,4-dioxane (15 ml)and concentrated hydrochloric acid (15) was heated to reflux for 72 h.The dioxane was removed by rotary evaporation and the product wascollected by suction filtration, washed with water to neutrality andair-dried to constant weight to give 315 mg (97%) of the title compoundas a tan to light brown solid. MS: m/e=305 (M−H)⁺.

Example 62c Preparation of 2ah

[1033] To a solution of example 2ag (75 mg, 0.25 mmol) in DMF (5 ml) andethanol (1 ml) was added a solution of (trimethylsilyl)diazomethane (2Min hexanes, 0.6 ml, 1.2 mmol). After being stirred for 4 h a few dropsof glacial acetic acid was added, the solvents were removed in-vacuo,and the residue was slurried in water (5 ml) and freeze-dried to provide11 mg (91%) of the title compound as a tan or light-brown solid. MS:m/e=319 (M−H)⁺.

Example 62d Preparation of 2ai

[1034] To a solution of example 2ag (20 mg, 0.065 mmol) in DMF (3 ml)was added 1-hydroxybenzotriazole (HOBt, 13 mg, 0.098) andbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 43 mg, 0.098 mmol). The mixture was stirred for 2h,N,N-dimethyethylenediamine (9 mg, 0.098 mmol) was added and stirring wascontinued for 1-3h or until deemed complete by HPLC analysis. Themixture was concentrated to an oily residue, washed thoroughly withether, dissolved into 0.5N HCl (5 ml), filtered to clarify andfreeze-dried to give 25 mg (93%) of the title compound. MS: m/e=377(M+H)⁺.

Example 62e Preparation of 2aj

[1035] This compound was prepared according to the procedure describedabove for example 2ai. From 2ag (20 mg, 0.065 mmol) and4-(2-aminoethyl)morpholine (13 mg, 0.098 mmol) was obtained 29 mg (97%)of the title compound. MS: m/e=419 (M+H)⁺.

Example 62f Preparation of 2ak

[1036] This compound was prepared according to the procedure describedabove for example 2ai except product isolation was achieved by dilutionof the reaction mixture with ethyl acetate (15 ml) and washing theresulting precipitate with ethyl acetate (2×5 ml) and ether (5 ml). Fromexample 2ag (20 mg, 0.065 mmol) and morpholine (7 mg, 0.078 mmol) wasobtained 4 mg (17%) of the title compound as a tan solid. MS: 376(M+H)⁺.

Example 62g Preparation of 2al

[1037] This compound was prepared according to the procedure describedabove for example 2ai except product isolation was achieved byevaporation of DMF, stirring the residue with methanol (3 ml) andwashing the resulting precipitate with 50% methanol/ether (5 ml) andether (5 ml). From example 2ag (20 mg, 0.065 mmol) and4-(N-methyl-aminomethyl)pyridine (12 mg, 0.098 mmol) was obtained 18 mg(67%) of the title compound as a light brown solid. MS: 411 (M+H)⁺.

Example 62 h Preparation of 2am

[1038] This compound was prepared according to the procedure describedabove for example 2ai except product isolation was achieved byevaporation of DMF, stirring the residue with 50% methanol/ether (2 ml)and washing the resulting precipitate with ether (2×3 ml). From example2ag (20 mg, 0.065 mmol) and N⁵⁸ -methylhistamine dihydrochloride (21 mg,0.104 mmol) was obtained 5 mg (19%) of the title compound as a lightbrown solid. MS: 414 (M+H)⁺.

Example 62i Preparation of 2an

[1039] This compound was prepared according to the procedure describedabove for example 2ai. From example 2ag (20 mg, 0.065 mmol) and2-(N-methyl-aminomethyl)pyridine (13 mg, 0.104 mmol) was obtained 27 mg(99%) of the title compound as a light brown solid. MS: m/e 411 (M+H)⁺.

Example 62j Preparation of 2ao

[1040] A mixture of5-triisopropylsilyloxy-2-(1-hydroxycyclopentyl)indole (0.4 g, 1 mmol)and maleimide (0.15 g, 1.6 mmol) in acetic acid were stirred for 24hours at room temperature. The mixture was concentrated at reducedpressure. The residue was dissolved in methylene chloride, washed with10% NaHCO₃ solution and dried (MgSO₄). The drying agent was removed byfiltration and the solvent concentrated to give 0.31 g MS: m/e 451(M−H)⁺. The Diels-Alder adduct (1.2 g, 2.6 mmol) in HOAc (60 mL) wasadded 30% H₂O₂ (15 mL) followed by heating for 90 minutes at 50° C. Themixture was concentrated then water added and a tan solid collected,1.07 g; MS: m/e 447 (M−H)⁺. The above carbazole (0.3 g, 0.66 mmol) andTBAF (1.67 mL of 1 M solution, 1.67 mmol) in CH₃CN (40 mL) were stirredfor 0.5 hours at room temperature. The solvent was concentrated atreduced pressure and the residue was partitioned between ethyl acetateand water. The ethyl acetate layer was dried (MgSO₄) and concentrated togive 0.13 g of 2ao. MS: m/e 291 (M−H)⁻.

Example 62k Preparation of 2ap

[1041] This compound was prepared by the same general procedure asdescribed for 2ao or 1a starting with5-methoxy-2-(1-hydroxycyclopentyl)indole to give 2ap. MS m/e=305 (M−H).

Example 62l Preparation of 2aq

[1042] This compound was prepared by the same general procedure asdescribed for 2ao or 1a starting with5-ethoxyethoxy-2-(1-hydroxycyclopentyl)indole to give 2aq. MS m/e=363(M−H).

Example 62m Preparation of 2ar

[1043] This compound was prepared by the same general procedure asdescribed for 2ao or 1a starting with5-diethylaminoethyloxy-2-(1-hydroxycyclopentyl)indole to give the titlecompound. MS m/e=392 (M−H)⁺.

Example 62n Preparation of 2as

[1044] This compound was prepared by the same general procedure asdescribed for 2ao or 1a starting with5-dimethylaminoethyloxy-2-(1-hydroxycyclopentyl)indole to give the titlecompound. MS m/e=378 (M+H).

Example 62o Preparation of 2at

[1045] This compound was prepared by the same general procedure asdescribed for 2ao or 1a starting with5-morpholinoethoxy-2-(1-hydroxycyclopentyl)indole to give the titlecompound. MS m/e=406 (M+H).

Examples 62p-62x Data for 2au-2bc

[1046] TABLE 9 Example Compound Mass Spec (m/e) 62p 2au 333 (M − H)⁻ 62q2av 303 (M − H)⁺ 62r 2aw 305 (M − H)⁻ 62s 2ax 319 (M − H)⁻ 62t 2ay 279(M + H)⁺ 62u 2az 303 (M − H)⁻ 62v 2ba 361 (M − H)⁻ 62w 2bb 347 (M − H)⁻62x 2bc 314 (M − H)⁻

Example 62y Preparation of 2bd

[1047] The carboxylation procedure of Neubert and Fishel [Org. Synth.Col. Vol. 7, 420-424 (1990)] was followed. Oxalyl chloride (1.0 mL, 1.45g, 11.4 mmol) was added to a stirred suspension of aluminum chloride(1.50 g, 11.3 mmol) in 1,2-dichloroethane (20 mL) at 20° C. After 1 min,1a (1.00 g, 3.62 mmol) was added and the mixture was stirred for 40 min,then poured into 20 g of ice and water (gas evolution) and stirred for10 min. The precipitate was collected by vacuum filtration and rinsedwith water, 1M HCl, and water, then dried to give 1.11 g (95% yield) ofcrude 2bd contaminated with 17% of the dimeric ketone. A pure sample of2bd was obtained by suspension in dilute aqueous Na₂CO₃ and filtrationfollowed by acidification with HC1. After several days, the resultinggel yielded a solid precipitate which was collected and dried. MS m/e319 (M−H)⁻; ¹H NMR (DMSO-d₆) δ2.29 (2H, m), 3.18 (2H, t), 3.26 (2H, t),7.62 (1H, d), 8.11 (1H, d), 9.48 (1H, s), 11.02 (1H, s), 12.27 (1H, s).

Examples 62z-62ad Data for 2be-2bj

[1048] TABLE 10 Example Compound Mass Spec (m/e) 62z 2be 320 (M + H)⁻62aa 2bf 289 (M − H)⁻ 62ab 2bg 392 (M + H)⁺ 62ac 2bh 318 (M − H)⁻ 62ad2bi 333 (M − H)⁻

Example 62ae Preparation of 2bj

[1049] NaBH₃CN (60 mg, 0.95 mmol) was added to a solution of thehydrochloride salt of 2p (300 mg, 0.88 mmol) and aqueous formaldehyde(0.10 mL, 37%, 1.23 mmol) in water (6 mL). After 2.5 h, the solution wasbasified with saturated Na₂CO₃. The precipitate was collected, rinsedwith water, and dried to afford 2bj (207 mg, 71% yield). MS m/z 334(M+H)⁺, 289 (M−Me₂N)⁺; NMR (DMSO-d₆) δ2.30 (2H, m), 3.18 (2H, t), 3.26(2H, t), 4.08 (2H, br.), 7.58 (2H, Abq), 8.82 (1H, s), 10.95 (1H, s),12.01 (1H, s).

Examples 62af-62as General Procedure for Preparation of 2bk-2bx

[1050] TABLE 11 Example Compound Mass Spec (m/e) 62af 2bk 334 (M + H)⁺62ag 2bl 390 (M + H)⁺ 62ah 2bm 362 (M + H)⁺ 62ai 2bn 418 (M + H)⁺ 62aj2bo 486 (M + H)⁺ 62ak 2bp 362 (M + H)⁺ 62al 2bq 396 (M + H)⁺ 62am 2br348 (M + H)⁺ 62an 2bs 418 (M + H)⁺ 62ao 2bt 320 (M + H)⁺ 62ap 2bu 348(M + H)⁺ 62aq 2bv 376 (M + H)⁺ 62ar 2bw 360 (M + H)⁺ 62as 2bx 374 (M +H)⁺

Examples 62at-62ba General Procedure for Preparation of 2by-2cf

[1051] TABLE 12 Example Compound Mass Spec (m/e) 62at 2by 416 (M + H)⁺62au 2bz 448 (M + H)⁺ 62av 2ca 475 (M − H)⁻ 62aw 2cb 377 (M − H)⁻ 6Zax2cc 482 (M − H)⁻ 62ay 2cd 444 (M − H)⁻ 62az 2ce 356 (M + Na) 62ba 2cf336 (M + H) 

Example 62bb Preparation of 2cg

[1052] Oxalyl chloride (0.010 mL, 14.5 mg, 0.114 mmol) was added tocrude 2bd (28 mg, 0.0875 mmol) in DMF (0.28 mL) 0° C. After 1 h at 20°C., excess HC1 was removed with a nitrogen stream, and2-(N,N-dimethylamino)ethylamine (24 mg, 0.27 mmol) was added. After 1 h,the precipitate was collected, dried, and suspended in 0.5 mL 0.1 M HCl.The precipitate (consisting of dimeric ketone in the crude startingmaterial) was discarded and the supernatant was lyophilized to give thehydrochloride of 2cg. MS m/z 391 (M+H)⁺; NMR (DMSO-d₆) δ2.31 (2H, m),2.88 (6H, d), 3.20 (2H, t), 3.27 (2H, t), 7.62 (1H, d), 8.04 (1H, d),8.71 (1H, br. S), 9.37 (1H, s), 9.65 (1H, br. s), 11,02 (1H, s), 12.24(1H, s).

Examples 62bc-62ca General Procedure for Preparation of 2ch-2df

[1053] TABLE 13 Example Compound Mass Spec (m/e) 62bc 2ch 405 (M + H)62bd 2ci 411 (M + H) 62be 2cj 414 (M + H) 62bf 2ck 451 (M + H) 62bg 2cl411 (M + H) 62bh 2cm 431 (M + H 62bi 2cn 433 (M + H 62bj 2co 376 (M − H)62bk 2cp 388 (M − H) 62bl 2cq 403 (M + H) 62bm 2cr 404 (M + H) 62bn 2cs388 (M + H) 62bo 2ct 418 (M + H) 62bp 2cu 405 (M + H) 62bq 2cv 425 (M +H) 62br 2cw 439 (M + H) 62bs 2cx 425 (M + H) 62bt 2cy 431 (M + H) 62bu2cz 392 (M + H) 62bv 2da 392 (M + H) 62bw 2db 446 (M + H) 62bx 2dc 408(M + H) 62by 2dd 400 (M − H) 62bz 2de 333 (M − H) 62ca 2df 412 (M + H)

Example 63 Preparation of 3a

[1054] A mixture of 2e (0.03 g, 0.08 mmol), thiourea (0.006 g, 0.08mmol) and ethanol (1 mL) was heated at 70° C. in a sealed tube for 1 h.On cooling, a precipitate appeared that was filtered, washed severaltimes with cold ethanol and ether, respectively and dried under highvacuum to generate 0.025 g of 3a. Compound 3a is characterized as ayellow amorphous solid; R_(t) 6.68 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H),11.00 (s, 1H), 9.00 (s, 1H), 7.75 (d, 1H), 7.50 (d, 1H), 7.00 (s, 1H),3.50 (broad, 2H), 3.25 (2sets of t, 4H), 2.25 (broad m, 2H). MS m/e 375(M+H).

Example 64 Preparation of 3b

[1055] A mixture of 2e (0.05 g, 0.13 mmol), thioacetamide (0.01 g, 0.13mmol) and ethanol (1 mL) was heated at 70° C. in a sealed tube for 1 h.On cooling, a precipitate appeared that was filtered, washed severaltimes with cold ethanol and ether, respectively and dried under highvacuum to generate 0.025 g of 3b. Compound 3b is characterized as ayellow amorphous solid; R_(t) 10.14 min; ¹H-NMR (DMSO-d₆) δ12.00 (s,1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.00 (d, 1H), 7.70 (s, 1H), 7.50 (d,1H), 3.25 (2 sets of t, 4H), 2.70 (s, 3H), 2.25 (broad m, 2H); MS m/e374 (M+H).

Example 65 Preparation of 3e

[1056] A mixture of 2e (0.03 g, 0.07 mmol), Boc-L-thiocitruline-OtBu(0.01 g, 0.13 mmol) and ethanol (1 mL) was heated at 70° C. in a sealedtube for 1h. On cooling, a precipitate appeared that was filtered,washed several times with cold ethanol and dried under high vacuum togenerate 0.010 g of 3e. Compound 3e is characterized as a yellowamorphous solid; R_(t) 12.23 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 10.90(s, 1H), 9.20 (s, 1H), 8.20 (broad, 3H), 8.00 (d, 1H), 7.80 (broad, 1H),7.50 (d, 1H), 6.80 (s, 1H), 4.00 (m, 1H), 3.50 (broad, 2H), 3.25 (2 setsof t, 4H), 2.25 (broad m, 2H), 1.70 (broad, 4H); MS m/e 646 (M+H).

Example 66 Preparation of 3c

[1057] A mixture of 3b (0.051 g, 0.136 mmol), N-bromosuccinamide (0.027g, 0.152 mmol) and DMF (3 mL) was stirred at room temperature for 72 h,poured into cold MeOH (6 mL) and filtered. The precipitated solid waswashed several times with small portions of cold methanol and driedunder high vacuum to generate 0.041 g of 3c. Compound 3c ischaracterized as a yellow amorphous solid; R_(t) 12.90 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 10.90 (s, 1H), 9.40 (s, 1H), 8.00 (d, 1H),7.60 (s, 1H), 3.25 (2 sets of t, 4H), 2.70 (s, 3H), 2.25 (broad m, 2H);MS m/e 452 and 454 (M+H for different isotopes of bromine).

Example 67 Preparation of 3d

[1058] A mixture of Example 2f (0.1 g, 0.24 mmol), thiourea (0.03 g, 0.4mmol) and ethanol (3 mL) was heated at 75-80° C. in a sealed tubeovernight. On cooling, a precipitate appeared that was filtered, washedseveral times with cold ethanol and ether and dried under high vacuum togenerate 0.075 g of 3d. Compound 3d is characterized as a yellowamorphous solid; R_(t) 8.07 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00(s, 1H), 9.00 (s, 1H), 8.80 (b, 2H), 7.70 (dd, 2H), 3.25 (2 sets oft,4H), 2.40 (s, 3H), 2.25 (broad m, 2H). MS m/e 389 (M+H).

Example 68 Preparation of 3f

[1059] A mixture of 3e (0.060 g, 0.093 mmol), trifluoroacetic acid (1mL) and water (2 drops) was stirred at room temperature for 2 h. Excessreagents were removed and the residue was triturated with ethyl acetate(5 mL) to generate a solid. Filtration and drying under high vacuumgenerated 0.048 g of 3f. Compound 3f is characterized as a yellowamorphous solid. R_(t) 6.64 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 10.90(s, 1H), 9.20 (s, 1H), 7.90 (d, 1H), 7.60 (d, 1H), 6.90 (s, 1H), 3.70(broad, 1H), 3.60 (broad, 4), 3.25 (2 sets of t, 4H), 2.25 (broad m,2H), 1.70 (broad, 4H); MS m/e 490 (M+H).

Example 69 Preparation of 3g

[1060] A mixture of 2e (0.053 g, 0.133 mmol), 2-imino-4-thiobiuret(0.017 g, 0.144 mmol) and ethanol (3 mL) was heated at 70° C. in asealed tube for overnight. On cooling, a precipitate appeared that wasfiltered, washed several times with cold ethanol and dried under highvacuum to generate 0.055 g of 3 g. Compound 3 g is characterized as ayellow amorphous solid; R_(t) 8.25 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H),10.90 (s, 1H), 9.30 (s, 1H), 8.20 (broad, 4H), 8.00 (d, 1H), 7.60 (d,1H), 7.50 (s, 1H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H); MS m/e417 (M+H).

Example 70 Preparation of 3h

[1061] A mixture of 2e (0.05 g, 0.126 mmol), methythiourea (0.016 g,0.133 mmol) and ethanol (3 mL) was heated at 75-80° C. in a sealed tubefor 1 h. On cooling, a precipitate appeared that was filtered, washedseveral times with cold ethanol and dried under high vacuum to generate0.03 g of 3h. Compound 3h is characterized as a yellow amorphous solid;R_(t) 7.92 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.10 (s,1H), 7.80 (d, 1H), 7.50 (d, 1H), 7.00 (s, 1H), 3.75 (broad, 1H), 3.25 (2sets of t, 4H), 2.40 (s, 3H), 2.25 (broad m, 2H). MS m/e 389 (M+H).

Example 71 Preparation of 3i

[1062] A mixture of 2e (0.05 g, 0.126 mmol), acetylthiourea (0.012 g,0.133 mmol) and ethanol (3 mL) was heated at 75-80° C. in a sealed tubefor 1 h. On cooling, a precipitate appeared that was filtered, washedseveral times with cold ethanol and dried under high vacuum to generate0.044 g of 3i. Compound 3i is characterized as a yellow amorphous solid;R_(t) 10.57 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 12.00 (s, 1H), 11.00(s, 1H), 9.30 (s, 1H), 8.00 (d, 1H), 7.60 (d, 1H), 7.40 (s, 1H), 3.25 (2sets of t, 4H). 2.25 (broad m, 2H), 2.10 (s, 3H). MS m/e 415 (M−H).

Example 72 Preparation of 3j

[1063] A mixture of 2e (0.037 g, 0.093 mmol), N-benzyloxythioglycinamide(0.028 g, 0.125 mmol) and ethanol (3 mL) was heated at 75-80° C. in asealed tube for 1 h. On cooling, a precipitate appeared that wasfiltered and washed with ether to give 0.029 g of 3j. Compound 3j ischaracterized as a brown amorphous solid; R_(t) 12.81 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.30 (t, 1H),8.00 (d, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.30 (m, 5H), 5.00 (s, 2H),4.50 (broad, 2H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H). MS m/e 545(M+Na), 523 (M+H).

Example 73 Preparation of 3k

[1064] A mixture of 3j (0.06 g, 0.115 mmol) and 30% HBr in HOAc (0.8 mL)was stirred at room temperature for 30 min. Excess reagent was removedand the residue was triturated with ether to give 0.052 g of 3k.Compound 3k is characterized as a yellow amorphous solid; R_(t) 7.36min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.60(broad, 3H), 8.10 (d, 1H), 8.00 (s, 1H), 7.60 (d, 1H), 4.50 (broad, 2H),3.25 (2 sets of t, 4H), 2.25 (broad m, 2H). MS m/e 389 (M+H).

Example 74 Preparation of 3l

[1065] A mixture of 2e (0.2 g, 5.037 mmol), acetylguanidine (0.153 g,1.51 mmol) and DMF (3 mL) was heated at 60° C. in a sealed tube for 1.5h, concentrated at high vacuum and triturated with water to give 0.189 gof a crude material. This material was washed with hot ethanol (3×75 mL)and dried under high vacuum to generate 0.039 g of 3l. Compound 3l ischaracterized as a brown amorphous solid; R_(t 7.41) min; ¹H-NMR(DMSO-d₆) δ11.80 (s, 1H), 11.60 (s, 1H), 11.30 (s, 1H), 10.80 (s, 1H),9.10 (s, 1H), 7.80 (d, 1H), 7.50 (d, 1H), 7.20 (s, 1H), 3.25 (2 sets oft, 4H), 2.25 (broad m, 2H), 2.10 (s, 3H). MS m/e 400 (M+H).

Example 75 Preparation of 3m

[1066] To a mixture of 3k (0.015 g, 0.032 mmol) and triethylamine (0.007g, 0.07 mmol) in DMF (1 mL) at room temperature was addedmethanesulfonyl chloride (0.004 g, 0.035 mmol). The mixture was stirredfor 30 min, poured over ice-water (1 mL) and filtered. The residue waswashed with water and ether and dried to generate 0.005 g of 3m.Compound 3m is characterized as a yellow amorphous solid; R_(t) 9.95min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.10(m, 2H), 7.80 (s, 1H), 7.60 (d, 1H), 4.50 (s, 2H), 3.25 (2 sets of t,4H), 2.40 (s, 3H), 2.25 (broad m, 2H). MS m/e 489 (M+Na), 467 (M+H).

Example 76 Preparation of 3n

[1067] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was added acetylchloride (0.007 g, 0.09 mmol). The mixture was stirred for 30 min,poured over ice-water (1 mL) and filtered. The residue was washed withwater and ether and dried to generate 0.01 g of 3n. The compound 3n ischaracterized as a yellow amorphous solid; R_(t) 9.31 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.70 (t, 1H),8.00 (d, 1H). 7.80 (s, 1H), 7.60 (d, 1H), 4.60 (s, 2H), 3.25 (2 sets oft, 4H), 2.25 (broad m, 2H), 1.90 (s, 3H). MS m/e 453 (M+Na), 431 (M+H).

Example 77 Preparation of 3o

[1068] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.01g, 0.094 mmol) in DMF (1 mL) at room temperature was added ethylisocyanate (0.0066 g, 0.09 mmol). The mixture was stirred for 30 min,poured over ice-water (1 mL) and filtered. The residue was washed withwater and ether and dried to generate 0.008 g of 3o. Compound 3o ischaracterized as a yellow amorphous solid; R_(t) 9.38 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.00 (d, 1H),7.80 (s, 1H), 7.60 (d, 1H), 7.40 (broad, 1H), 6.70 (broad, 1H), 4.50 (s,2H), 3.25 (2 sets of t, 4H), 3.10 (q, 2H), 2.25 (broad m, 2H), 1.00 (t,3H). MS m/e 482 (M+Na), 460 (M+H),

Example 78 Preparation of 3p

[1069] A mixture of 2e (0.05 g, 0.126 mmol),2-(t-butanesulfonyl)thioacetamide (0.026 g, 0.132 mmol) and ethanol (2mL) was heated at 75-80° C. in a sealed tube overnight. On cooling, aprecipitate appeared that was filtered, washed several times with ethylacetate and ether and dried under high vacuum to generate 0.02 g of 3p.Compound 3p is characterized as a yellow amorphous solid; R_(t) 11.73min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.10(d, 1H), 8.00 (s, 1H), 7.60 (d, 1H), 5.00 (s, 2H), 3.25 (2 sets of t,4H), 2.25 (broad m, 2H), 1.30 (s, 9H). MS m/e 516 (M+Na), 494 (M+H).

Example 79 Preparation of 3q

[1070] A mixture of 2e (0.05 g, 0.126 mmol),2-(t-butoxycarbonyl)thioacetamide (0.024 g, 0.137 mmol) and ethanol (2mL) was heated at 75-80° C. in a sealed tube overnight. On cooling, aprecipitate appeared that was filtered, washed several times with ethylacetate and ether and dried under high vacuum to generate 0.02 g of 3q.Compound 3q yellow amorphous solid; R_(t) 14.48 min; ¹H-NMR (DMSO-d₆)δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.10 (d, 1H), 7.90 (s, 1H),7.60 (d, 1H), 5.50 (s, 2H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H),1.20 (s, 9H). MS m/e 496 (M+Na), 474 (M+H).

Example 80 Preparation of 3r

[1071] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was added isovalerylchloride (0.011 g, 0.094 mmol). The mixture was stirred overnight,concentrated at the rotavap, triturated with water (1 mL) and filtered.The residue was washed with water and ether and dried to generate 0.019g of 3r. Compound 3r is characterized as a yellow amorphous solid; R_(t)11.25 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H),8.70 (t, 1H), 8.00 (d, 1H), 7.70 (s, 1H), 7.50 (d, 1H), 4.60 (d, 2H),3.25 (2 sets of t, 4H), 2.20 (m, 3H), 2.00 (broad, 2H), 0.90 (d, 6H). MSm/e 495 (M+Na), 473 (M+H).

Example 81 Preparation of 3s

[1072] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was added propionylchloride (0.009 g, 0.094 mmol). The mixture was stirred overnight,concentrated at the rotavap, triturated with water (1 mL) and filtered.The residue was washed with water and ether and dried to generate 0.019g of 3s. Compound 3s is characterized as a yellow amorphous solid; R_(t)9.97 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H),8.70 (t, 1H), 8.00 (d, 1H), 7.70 (s, 1H), 7.50 (d, 1H), 4.60 (d, 2H),3.25 (2 sets of t, 4H), 2.25 (broad m, 4H), 1.00 (d, 3H). MS m/e 467(M+Na), 445 (M+H).

Example 82 Preparation of 3t

[1073] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was added isobutyrylchloride (0.010 g, 0.094 mmol). The mixture was stirred overnight,concentrated at the rotavap, triturated with water (1 mL) and filtered.The residue was washed with water and ether and dried to generate 0.007g of 3t. Compound 3t is characterized as a yellow amorphous solid; R_(t)10.52 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H),8.70 (broad t, 1H), 8.00 (d, 1H), 7.70 (s, 1H), 7.50 (d, 1H), 4.60 (d,2H), 3.25 (2 sets of t, 4), 3.00 (m, 1H), 2.25 (broad m, 2H), 1.00 (d,6H). MS m/e 481 (M+Na), 458 (M+H).

Example 83 Preparation of 3u

[1074] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was added butyrylchloride (0.010 g, 0.094 mmol). The mixture was stirred overnight,concentrated at the rotavap, triturated with water (1 mL) and filtered.The residue was washed with water and ether and dried to generate 0.019g of 3u. Compound 3u is characterized as a yellow amorphous solid; R_(t)10.64 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H),8.70 (broad t, 1H), 8.00 (d, 1H), 7.70 (s, 1H), 7.50 (d, 1H), 4.60 (d,2H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H), 2.10 (t, 2H), 1.50 (m,2H), 0.70 (t, 3H). MS m/e 481 (M+Na), 458 (M+H).

Example 84 Preparation of 3v

[1075] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was added valerylchloride (0.011 g, 0.094 mmol). The mixture was stirred overnight,concentrated at the rotavap, triturated with water (1 mL) and filtered.The residue was washed with water and ether and dried to generate 0.021g of 3v. Compound 3v is characterized as a yellow amorphous solid; R_(t)11.40 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.30 (s, 1H),8.70 (t, 1H), 8.00 (d, 1H), 7.70 (s, 1H), 7.50 (d, 1H), 4.60 (d, 2H),3.25 (2 sets of t, 4H), 2.25 (broad m, 2H), 2.10 (t, 2H), 1.50 (m, 2H),1.20 (m, 2H), 0.70 (t, 3H). MS m/e 495 (M+Na), 473 (M+H).

Example 85 Preparation of 3w

[1076] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was addedcyclopropanecarbonyl chloride (0.010 g, 0.094 mmol). The mixture wasstirred overnight, concentrated at the rotavap, triturated with water (1mL) and filtered. The residue was washed with water and ether and driedto generate 0.017 g of 3w. Compound 3w is characterized as a yellowamorphous solid; R_(t) 10.34 min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00(s, 1H), 9.30 (s, 1H), 9.00 (broad t, 1H), 8.00 (d, 1H), 7.75 (s, 1H),7.60 (d, 1H), 4.60 (d, 2H), 3.25 (m, 4H), 2.25 (broad m, 2H), 1.60 (m,1H), 0.70 (broad, 4H). MS m/e 479 (M+Na), 457 (M+H).

Example 86 Preparation of 3x

[1077] To a mixture of 3k (0.04 g, 0.085 mmol) and triethylamine (0.019g, 0.18 mmol) in DMF (1 mL) at room temperature was addedcyclopentanecarbonyl chloride (0.012 g, 0.094 mmol). The mixture wasstirred overnight, concentrated at the rotavap, triturated with water (1mL) and filtered. The residue was washed with water and ether and driedto generate 0.016 g of 3x. Compound 3x is characterized as a yellowamorphous solid; R_(t) 11.59 min. ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00(s, 1H), 9.30 (s, 1H), 8.70 (broad t, 1H), 8.00 (d, 1H), 7.75 (s, 1H),7.50 (d, 1H), 4.50 (d, 2H), 3.25 (m, 4H), 2.60 (m, 1H), 2.25 (broad m,2H), 1.80-1.30 (m, 8H). MS m/e 507 (M+Na), 485 (M+H).

Example 87 Preparation of 3y

[1078] A mixture of 2e (0.042 g, 0.106 mmol),2-(t-butylcarbonyloxy)thioacetamide (0.022 g, 0.126 mmol) and ethanol (3mL) was heated at 75-80° C. in a sealed tube for 2 h. On cooling, aprecipitate appeared that was filtered and washed several times withcold ethanol. The combined filtrate and washings were concentrated athigh vacuum to generate 0.018 g of 3y. Compound 3y is characterized as ayellow amorphous solid; R_(t) 15.67 min; ¹H-NMR (DMSO-d₆) δ12.00 (s,1H), 11.00 (s, 1H), 9.30 (s, 1H), 8.10 (d, 1H), 7.90 (s, 1H), 7.60 (d,1H), 5.50 (s, 2H), 3.25 (2 sets of t, 4H), 2.25 (broad m, 2H), 1.20 (s,9H). MS m/e 472 (M−H).

Example 88 Preparation of 3z

[1079] A mixture of 2e (0.04 g, 0.1 mmol),2-(methylsulfonyl)thioacetamide (0.019 g, 0.12 mmol) and ethanol (3 mL)was heated at 75-80° C. in a sealed tube for 2 h. On cooling, aprecipitate appeared that was filtered, washed several times with coldethanol and dried under high vacuum to generate 0.033 g of 3z. Compound3z is characterized as a yellow amorphous solid; R_(t) 11.24 min; ¹H-NMR(DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H),8.00 (s, 1H), 7.60 (d, 1H), 5.20 (s, 2H), 3.60 (s, 3H), 3.25 (2 sets oft, 4H), 2.25 (broad m, 2H). MS m/e 450 (M−H).

Example 89 Preparation of 3aa

[1080] A mixture of 2e (0.044 g, 0.1108 mmol),isoxazole-5-thiocarboxamide (0.017 g, 0.1328 mmol) and ethanol (3 mL)was heated at 75-80° C. in a sealed tube for 2 h. On cooling, aprecipitate appeared that was filtered, washed several times with coldethanol and dried under high vacuum to generate 0.036 g of 3aa. Compound3aa is characterized as a yellow amorphous solid; R_(t) 13.77 min;¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.80 (s,1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.60 (d, 1H), 7.20 (s, 1H), 3.25 (2sets of broad, 4H), 2.25 (broad m, 2H). MS m/e 425 (M−H).

Example 90 Preparation of 3ab

[1081] A mixture of 2e (0.044 g, 0.1108 mmol),N-[3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]thiourea(0.032 g, 0.1344 mmol) and ethanol (3 mL) was heated at 75-80° C. in asealed tube for 2 h. On cooling, a precipitate appeared that wasfiltered, washed several times with cold ethanol and dried under highvacuum to generate 0.053 g of 3ab. Compound 3ab is characterized as ayellow amorphous solid; R_(t) 6.88 min; ¹H-NMR (DMSO-d₆) spectrum is acomplex one. MS m/e 537 (M+H).

Example 91 Preparation of 4a

[1082] A mixture of 2e (0.042 g, 0.106 mmol), L-proline methyl esterhydrochloride (0.028 g, 0.169 mmol) and N-methylmorpholine (0.032 g,0.32 mmol) in dry DMF (3 mL) was stirred at 60° C. for 4 h, poured intoa mixture of ice and water (ca. 20 g) and filtered. The filtrate wasthen extracted into ethyl acetate-THF (1:1, 2×20 mL). The combinedorganic layer was dried (MgSO4) and concentrated to give a residue,which on trituration with ethyl acetate (4 mL) generated 0.008 g of 4a.Compound 4a is characterized as a yellow amorphous solid; R_(t) 8.82 min(broad); ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H),8.10 (d, 1H), 7.50 (d, 1H), 4.30 (d, 1H), 4.10 (d, 1H), 3.60 (m, 1H),3.50 (s, 3H), 3.25 (2 sets of t, 4H), 2.70 (q, 1H), 2.25 (broad m, 2H),2.10 (m, 1H), 1.70 (m, 4H); MS m/e 446 (M+H).

Example 92 Preparation of 4b

[1083] A mixture of 2e (0.1 g, 0.25 mmol), L-Pro-OtBu (0.048 g, 0.28mmol), triethylamine (0.028 g, 0.28 mmol) in DMF (2 mL) was stirred atroom temperature for 1 h, poured over ice-water (4 mL) and filtered. Theresidue was washed with water and ether, respectively, and dried underhigh vacuum to generate 0.068 g of 4b. Compound 4b is characterized as ayellow amorphous solid; R_(t) 9.73 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H),11.00 (s, 1H), 9.50 (s, 1H), 8.20 (d, 1H), 7.60 (d, 1H), 4.20 (dd, 2H),3.50 (m, 1H), 3.30 (m, 1H), 3.25 (2 sets of t, 4H), 3.00 (m, 1H), 2.80(m, 1H), 2.25 (broad m, 2H), 2.00 (m, 1H), 1.80 (m, 2H), 1.30 (s, 9H).MS m/e 488 (M+H).

Example 93 Preparation of 4c

[1084] A mixture of 4b (0.063 g, 0.13 mmol) and TFA (1 mL) was stirredat room temperature overnight. Excess reagent was removed and theresidue was triturated with ethyl acetate to generate 0.05 g of 4c.Compound 4c is characterized as a yellow amorphous solid; R_(t) 6.64min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.20(d, 1H), 7.60 (d, 1H), 4.80 (dd, 2H), 4.20 (broad, 1H), 3.50 (broad,1H), 3.40-2.80 (m, 6H), 2.25 (broad m, 2H), 2.00 (m, 4H). MS m/e 432(M+H).

Example 94 Preparation of 4d

[1085] A mixture of 2m (0.02 g, 0.053 mmol), NMM (0.011 g, 0.1 mmol),TBTU (0.034 g, 0.1 mmol) in dry DMF (2 mL) was stirred for 5 min. Asolution of H₂N(CH₂)₂NHtBoc (0.01 g, 0.054 mmol) in DMF (1 mL) was addedto the reaction flask and the mixture was stirred at room temperatureovernight. It was then poured into water (5 mL) and filtered. Theresidue was washed with small volumes of water and ether, respectively,and dried under high vacuum to generate 0.015 g of 4d. Compound 4d ischaracterized as a yellow amorphous solid; R_(t) 11.19 min; ¹H-NMR(DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H),8.00 (broad, 1H), 7.50 (d, 1H), 6.70 (broad, 1H), 3.40-2.70 (a series ofm, 8H), 2.50 (m, 4H), 2.25 (broad m, 2H), 1.20 (s, 9H). MS m/e 517(M−H).

Example 95 Preparation of 4e

[1086] A mixture of 4d (0.012 g, 0.02 mmol) and 4 N HCl in dioxane (3mL) was stirred at room temperature for 30 min and filtered. The residuewas washed with small volumes of dioxane and ether and dried under highvacuum to generate 0.008 g of 4e. Compound 4e is characterized as ayellow amorphous solid; R_(t) 7.23 min; ¹H-NMR (DMSO-d₆) δ12.30 (s, 1H),11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H), 8.20 (broad t, 1H), 8.00(broad, 3H), 7.60 (d, 1H), 3.40-2.50 (a series of m, 12H), 2.25 (broadm, 2H). MS m/e 417 (M−H).

Example 96 Preparation of 4f

[1087] This compound was prepared in a similar procedure to thatdescribed for 4d. Accordingly, the reaction between 2m (0.05 g) andmorpholine (0.015 g) in presence of TBTU and NMM in DMF generated 0.012g of 4f. Compound 4f is characterized as a yellow amorphous solid; R_(t)9.84 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.50 (s, 1H),8.10 (d, 1H), 7.60 (d, 1H), 3.70-3.00 (a series of m, 14H), 2.70 (m,2H), 2.25 (broad m, 2H). MS m/e 444 (M−H).

Example 97 Preparation of 4 g

[1088] This compound was prepared in the same manner as described for4d. Accordingly, the reaction between 2m (0.05 g) and ethanolamine(0.011 g) in presence of TBTU and NMM in DMF generated 0.027 g of 4 g.Compound 4 g is characterized as a yellow amorphous solid; R_(t) 7.62min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10(d, 1H), 7.90 (broad, 1H), 7.50 (d, 1H), 4.60 (t, 1H), 3.50-3.00 (aseries of m, 10H), 2.50 (t, 2H), 2.25 (broad m, 2H). MS m/e 418 (M−H).

Example 98 Preparation of 4 h

[1089] This compound was prepared in the same manner as described for4d. Accordingly, the reaction between 2m (0.05 g) and L-Pro-OtBu (0.030g) in presence of TBTU and NMM in DMF generated 0.058 g of 4h. Compound4h is characterized as a yellow amorphous solid; R_(t) 11.58 min; ¹H-NMR(DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H),7.50 (d, 1H), 4.60 and 4.20 (2 sets of rotameric m, 1H), 3.70-1.70 (aseries of m, 16H), 1.50 and 1.30 (2 sets of rotameric s, 9H). MS m/e 528(M−H).

Example 99 Preparation of 4i

[1090] This compound was prepared in the same manner as for 4d.Accordingly, the reaction between 2m (0.05 g) and diethylamine (0.013 g)in presence of TBTU and NMM in DMF generated 0.030 g of 4i. Compound 4iis characterized as a yellow amorphous solid; R_(t) 9.95 min; ¹H-NMR(DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10 (d, 1H),7.50 (d, 1H), 3.50-3.00 (a series of m, 10H), 2.70 (m, 2H), 2.20 (m,2H), 1.20 and 1.00 (2 sets of rotameric t, 6H). MS m/e 430 (M−H).

Example 100 Preparation of 4j

[1091] A mixture of 4h (0.05 g, 0.09 mmol), TFA (1 mL) and H₂O (2 drops)was stirred at room temperature for 45 min. Excess reagents were removedand the residue was triturated with methanol. Precipitated solid wasfiltered, washed with ether and dried under high vacuum to generate0.017 g of 4j. Compound 4j is characterized as a yellow amorphous solid;R_(t) 7.99 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s,1H), 8.10 (d, 1H), 7.50 (d, 1H), 4.60 and 4.20 (2 sets of rotameric m,1H), 3.70-1.70 (a series of m, 16H). MS m/e 472 (M−H).

Example 101 Preparation of 4k

[1092] To a suspension of AlCl₃ (0.8 g, 0.006 mol) in 1,2-dichloroethane(5 mL) at 0° C. was added 2,3-pyrazinedicarboxylic anhydride (0.49 g,0.0033 mol) and the mixture was stirred for 5 min. A suspension of 1a(0.3 g, 0.0011 mol) in 1,2-dichloroethane (15 mL) was slowly added tothe reaction flask. The cooling bath was removed and the mixture wasstirred at room temperature overnight; TLC of the reaction mixtureshowed unreacted starting materials. The reaction mixture was thenheated at 80° C. for 72 h, poured over a mixture of ice (ca. 10 g) and 2N HCl (10 mL) and filtered. The residue was washed with water and ether,respectively and dried under vacuum to generate 0.372 g of 4k. Compound4k is characterized as a yellow amorphous solid; R_(t) 7.29 min; ¹H-NMR(DMSO-d₆) δ12.30 (s, 1H), 11.00 (s, 1H), 9.20 (s, 1H), 9,00 (s, 2H),8.00 (d, 1H), 7.60 (d, 1H), 3.25 (2 sets of m, 4H), 2.25 (broad m, 2H).MS m/e 425 (M−H).

Example 102 Preparation of 4l

[1093] A mixture of 2m (0.05 g, 0.133 mmol), hydrazine (0.006 g) andethanol was heated at 80° C. in a sealed-tube overnight, cooled to 0° C.and filtered. The residue was washed with cold ethanol and ether,respectively and dried under high vacuum to generate 0.023 g of 4l.Compound 4l is characterized as a yellow amorphous solid; R_(t) 8.03min; ¹H-NMR (DMSO-d₆) δ12.00 (s, 1H), 10.90 (s, 1H), 10.80 (s, 1H), 9.10(s, 1H), 8.00 (d, 1H), 7.50 (d, 1H), 3.40-3.25 (3 sets of t, 6H), 2.50(t, 2H), 2.25 (broad m, 2H). MS m/e 371 (M−H).

Example 103 Preparation of 4m

[1094] This compound was prepared following the same procedure asdescribed for 4l. Accordingly, the reaction between 2m (0.05 g) andmethyl hydrazine (0.012 g) in ethanol generated 0.017 g of 4m. Compound4m is characterized as a yellow amorphous solid; R_(t) 10.21 min; ¹H-NMR(DMSO-d₆) δ12.10 (s, 1H), 11.00 (s, 1H), 9.20 (s, 1H), 8.00 (d, 1H),7.50 (d, 1H), 3.40-3.25 (m, 6H), 2.60 (t, 2H), 2.50 (s, 3H), 2.25 (broadm, 2H). MS m/e 385 (M−H).

Example 104 Preparation of 4n

[1095] To a suspension of AlCl₃ (0.667 g, 0.005 mol) in1,2-dichloroethane (5 mL) at 0° C. was added glutaric anhydride (0.57 g,0.005 mol) and the mixture was stirred for 5 min. A suspension of 1a(0.276 g, 0.001 mol) in 1,2-dichloroethane (15 mL) was slowly added tothe reaction flask. The cooling bath was removed and the mixture wasstirred at room temperature overnight; TLC of the reaction mixtureshowed unreacted starting materials. The reaction mixture was thenheated at 80° C. for 24 h, poured over a mixture of ice (ca. 10 g) and 2N HCl (10 mL) and filtered. The residue was washed with water and ether,respectively and dried under vacuum to generate 0.243 g of 4n. Compound4n is characterized as a yellow amorphous solid; R_(t) 8.84 min; ¹H-NMR(DMSO-d₆) δ12.30 (s, 1H), 12.00 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H),8.10 (d, 1H), 7.50 (d, 1H), 3.50-3.25 (m, 6H), 2.30 (t, 2H), 2.25 (broadm, 2H), 2.00 (m, 2H). MS m/e 389 (M−H).

Example 105 Preparation of 4o

[1096] This compound was prepared following the same procedure as for4d. Accordingly, the reaction between 2m (0.03 g) and L-Pro-NH₂ (0.016g) in the presence of TBTU and NMM in DMF generated 0.007 g of 4o.Compound 4o is characterized as a yellow amorphous solid; R_(t) 7.61min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10(d, 1H), 7.50 (d, 1H), 7.20 (d, 1H), 6.80 (s, 1H), 4,40 and 4.20 (2 setsof rotameric m, 1H), 3.70-2.50 (a series of m, 10H), 2.25 (broad m, 2H),1.80 (m, 4H). MS m/e 471 (M−H).

Example 106 Preparation of 4p

[1097] This compound was prepared following the same procedure as for4d. Accordingly, the reaction between 2m (0.03 g) and piperidine (0.009g) in the presence of TBTU and NMM in DMF generated 0.011 g of 4p.Compound 4p is characterized as a yellow amorphous solid; R_(t) 11.61min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40 (s, 1H), 8.10(d, 1H), 7.50 (d, 1H), 3.50 (m, 2H), 3.30-3.00 (m, 8H), 2.60 (m. 2H),2.25 (broad m, 2H), 1.60 (broad m, 4H), 1.40 (broad m, 2H). MS m/e 442(M−H).

Example 107 Preparation of 4q

[1098] This compound was prepared following the same procedure asdescribed for 4d. Accordingly, the reaction between 2m (0.1 g) and4-t-butoxycarbonylpiperizine (0.1 g) in the presence of TBTU and NMM inDMF generated 0.112 g of 4q. Compound 4q is characterized as a yellowamorphous solid; R_(t) 11.87 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00(s, 1H), 9.40 (s, 1H), 8.10 (d, 1H), 7.50 (d, 1H), 3.50-2.70 (a seriesof m, 16H), 2.25 (broad m, 2H), 1.40 (s, 9H). MS m/e 543 (M−H).

Example 108 Preparation of 4r

[1099] A mixture of 4q (0.1 g, 0.184 mmol) and 4 N HCl in dioxane (3 mL)was stirred at room temperature for 30 min and filtered. The residue waswashed with small volumes of dioxane and ether and dried under highvacuum to generate 0.071 g of 4r. Compound 4r is characterized as ayellow amorphous solid; R_(t) 6.68 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H),11.00 (s, 1H), 9.40 (s, 1H), 9.30 (2 sets of broad, 2H), 8.10 (d, 1H),7.50 (d, 1H), 3.70-2.80 (a series of m, 16H), 2.25 (broad m, 2H). MS m/e443 (M−H).

Example 109 Preparation of 4s

[1100] This compound was prepared following the same procedure asdescribed for 4d. Accordingly, the reaction between 2m (0.05 g) andheptamethyleneimine (0.02 g) in the presence of TBTU and NMM in DMFgenerated 0.037 g of 4s. Compound 4s is characterized as a yellowamorphous solid; R_(t) 12.95 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00(s, 1H), 9.40 (s, 1H), 8.10 (d, 1H), 7.50 (d, 1H), 3.50 (m, 2H),3.30-3.00 (m, 8H), 2.60 (m, 2H), 2.25 (broad m, 2H), 1.80 (broad m, 2H),1.60 (2 sets of m, 8). MS m/e 470 (M−H).

Example 110 Preparation of 4t

[1101] This compound was prepared following the same procedure asdescribed for 4d. Accordingly, the reaction between 2m (0.05 g) andpyrrolidine (0.013 g) in the presence of TBTU and NMM in DMF generated0.033 g of 4t. Compound 4t is characterized as a yellow amorphous solid;R_(t) 10.18 min; ¹H-NMR (DMSO-d₆) δ12.20 (s, 1H), 11.00 (s, 1H), 9.40(s, 1H), 8.10 (d, 1H), 7.50 (d, 1H), 3.50 (m, 2H), 3.30-3.00 (m, 8H),2.60 (m, 2H), 2.25 (broad m, 2H), 1.80 (2 sets of m, 4H). MS m/e 428(M−H).

Example 111 Preparation of Precursors to 5a Ethyl5-Cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-4-carboxylate andEthyl 4-Cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate

[1102] 2-(Cyclopenten-1-yl)indole (13.6 g, 74 mmol), ethylcis-3-cyanoacrylate (17.8 g, 142 mmol) and BHT (70 mg) were heated to180° C. under nitrogen for 30 min. The volatiles were removed bykugelrohr distillation at 110° C. and 0.8 mm to afford 19.7 g of anamber-brown tar. Addition of ether (50 mL) afforded a precipitate of asingle isomer of white crystalline ethyl4-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate (1.89g, 8.2% yield); mp 192-195° C. NMR (CDCl₃) δ7.91 (s, 1H), 7.46 (d, 1H),7.34 (d, 1H), 7.12 (m, 2H), 4.31 (d, 1HO, 4.32 (m, 2H), 4.20 (d, 1H),3.46 (t, 1H), 3.30 (q, 1H), 2.80 (m, 1H), 2.3-1.4 (m, 6H), 1.34 (t, 3H).Anal. Calcd for C₁₉H₂₀N₂O₂; C, 74.00; H, 6.54; N, 9.08. Found: C, 73.84;H, 6.53; N, 9.03.

[1103] The filtrate was chromatographed on 500 g silica gel(ether-hexanes, 50:50 to 60:40) to afford 6.4 g (28% yield) ofdiastereomeric ethyl5-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-4-carboxylate as ayellow glass, a single white crystalline isomer of which (1.07 g, 4.7%yield) could be obtained by precipitation from ether (20 mL); mp164-167° C. MS m/e 309 (M+H)⁺. NMR (CDCl₃) δ8.08 (s, 1H), 7.58 (d, 1H),7.33 (d, 1H), 7.20 (m, 2H), 4.40 (d, 1HO, 4.32 (m, 2H), 3.16 (q, 1H),3.02 (q, 1H), 2.80 (dd, 1H), 2.1 (m, 3H), 1.9-1.4 (m, 7H), 1.39 (t, 3H).Anal. Calcd for C₁₉H₂₀N₂O₂-0.3Et₂O: C, 73.39; H, 7.01; N, 8.47. Found:C, 73.43; H, 6.54; N, 8.04 .

[1104] Further elution (ether-hexanes, 60:40) afforded more than 1.5 g(6.6%) of diastereomeric ethyl4-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate. MSm/e 309 (M+H)⁺.

Example 112 Preparation of Precursor to 5a Ethyl5-Cyano-1,2,3,10-tetrahydrocyclopenta[a]carbazole4-carboxylate

[1105] DDQ (1.35 g, 5.95 mmol) was added to solution of5-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-4-carboxylate (820mg, 2.66 mmol) in toluene (12 mL). The solution immediately turned darkbrown, and was stirred at 60° C. for 3 hr. The mixture was cooled to 20°C. overnight and filtered. The precipitate was rinsed twice with hexanesto give 2.04 g of a light green solid. This was suspended in methanol (8mL), filtered, and the precipitate rinsed with methanol (3 mL, inportions), and ether to give 603 mg (75.% yield) of product as a lightgreen solid, mp 233-234° C. NMR (CDCl₃) δ8.80 (d, 1H), 8.20 (s, 1H),7.52 (m, 2H), 7.38 (t, 1H), 4.52 (q, 2H), 3.42 (t, 2H), 3.19 (t, 2H),2.31 (quintet, 2H), 1.51 (t, 3H). Anal. Calcd for C₁₉H₁₆N₂O₂-0.2H₂O: C,74.11; H, 5.37; N, 9.10. Found: C, 74.03; H, 5.06; N, 9.04.

Example 113 Preparation of 5a5,7,8,9,10,11-Hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1106] Ethyl5-cyano-1,2,3,10-tetrahydrocyclopenta[a]carbazole-4-carboxylate (950 mg)in DMF (60 mL) was hydrogenated at 55 psi over W2 Raney nickel for twoweeks. A total of 15 g Raney nickel was added portionwise duringhydrogenation until starting material was consumed. The catalyst wasremoved by filtration and the DMF was evaporated in vacuo. The solidresidue was refluxed for 10 min with 30 mL water and cooled. Theprecipitate was rinsed with 5 mL acetone to give the product (640 mg,78% yield) as a white solid, mp 326-327° C. NMR (DMSO-d₆) δ11.6 (s, 1H),7.96 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.24 (t, 1H), 4.79 (s, 2H),3.30 (t, 2H), 3.11 (t, 2H), 2.26 (quintet, 2H). Anal. Calcd forC₁₇H₁₄N₂O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.35; H, 5.36; N,10.57.

Example 114 Preparation of 5b3-Bromo-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1107] N-Bromosuccinimide (190 mg, 1.07 mmol) was added to5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one(250 mg, 0.954 mmol) dissolved in DMF (7.5 mL). After 24 hr, the solventwas evaporated and the residue refluxed with water (5 mL) for 5 min.After cooling to 20° C., the precipitate was collected, affording theproduct (328 mg, 100% yield) as a yellow solid, mp˜350° C. (d). MS m/e341, 343 (M+H)⁺. NMR (DMSO-d₆) δ11.72 (s, 1H), 8.29 (s, 1H), 8.07 (s,1H), 7.51 (ABq, 2H), 4.80 (s, 2H), 3.32 (t, 2H), 3.20 (t, 2H), 2.30(quintet, 2H). Anal. Calcd for C₁₇H₁₃N₂OBr-0.75H₂O: C, 57.56; H, 4.12;N, 7.90. Found: C, 57.55; H, 3.89; N, 8.08.

Example 115 Preparation of 5c3-Cyano-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1108] Tetrakis(triphenylphosphine)palladium (70 mg, 0.061 mmol) wasadded under nitrogen to a mixture of3-bromo-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one(140 mg, 0.42 mmol) and Zn(CN)₂, (100 mg, 0.85 mmol) suspended in DMF (2mL). (See D. M. Tschaen, R. Desmond, A. O. King, M. C. Fortin, B. Pipik,S. King, and T. R. Verhoeven. Synth. Commun. 1994, 24, 887). The mixturewas heated to 125° C. for 2 hr, cooled to 20° C., then filtered througha mixture of diatomaceous earth and silica gel. The filtrate was dilutedwith 3 volumes water. The precipitate was collected and triturated twicewith ether to give the product (116 mg, 99% yield) as a yellow solid, mp369-370° C. NMR (DMSO-d₆) δ12.19 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H),7.80 (d, 1H), 7.69 (d, 1H), 4.85 (s, 2H), 3.30 (t, 2H), 3.12 (t, 2H),2.26 (quintet, 2H). MS m/e 288 (M+H)⁺.

Example 116 Preparation of 5d3-(Aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1109]3-Cyano-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one(95 mg, 0.33 mmol) dissolved in DMF (3 mL) was hydrogenated at 55 psiover freshly prepared (R. Mozingo, Org. Synth. Col. 1955, 3, 181-183)W-2 Raney nickel (310 mg) for 20 hr. The catalyst was removed and thesolvent evaporated to afford a residue which was suspended in water togive crude product (58 mg, 60% yield). NMR (DMSO-d₆) δ11.59 (s, 1H),8.29 (s, 1H), 7.96 (s, 1H), 7.53 (ABq, 2H), 4.75 (s, 2H), 4.00 (s, 2H),3.35 (t, 2H), 3.18 (t, 2H), 2.25 (quintet, 2H). MS m/e 275 (M+H−NH₃)⁺,292 (M+H)⁺. A portion of the crude product (12 mg) was stirred with 0.1M HCl (120 mL) and the filtrate was lyophilized to give thehydrochloride salt (9 mg).

Example 117 Preparation of 5e3-Methyl-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1110] Tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) wasadded under nitrogen to a mixture of3-bromo-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one(59 mg, 0.17 mmol) and tetramethyltin (38 mg, 0.20 mmol) in DMF (2 mL).The mixture was heated to 140° C. for 4 hr, cooled to 20° C., thenfiltered through a mixture of diatomaceous earth and silica gel. Thesolvent was evaporated from the filtrate, and the product, a yellowsolid, was isolated by chromatography (EtOAc-EtOH, 75:25). MS m/e 277(M+H)⁺.

Example 118 Preparation of 5f3-[(Bis(t-butoxycarbonyl)-L-lysyl)aminomethyl]-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1111] Di(BOC)-L-lysine dicyclohexylamine salt (70 mg, 0.133 mmol), HOBThydrate (15 mg, 0.098 mmol), and BOP reagent (60 mg, 0.136 mmol) wereadded to3-(aminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one(25 mg, 0.0859 mmol) dissolved in DMF (0.6 mL). After 5 hr, water (2.5mL) was added. The precipitate was suspended in ethyl acetate (10 mL)and the resulting filtrate was rinsed with 1 M HCl, water, and saturatedNa₂CO₃, then saturated NaCl. Evaporation of the solvent followed bychromatography (EtOAc-EtOH 100:0 to 95:5) gave the product as a lightyellow solid (12 mg, 22% yield). MS m/e 620 (M+H)⁺.

Example 119 Preparation of 5g3-Lysylaminomethyl)-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]-carbazole-7(6H)-one,dihydrochloride

[1112] The BOC groups of 5f were hydrolyzed with 2 M HCl in dioxane toafford the product as a beige solid (94% yield). NMR (DMSO-d₆) δ11.67(s, 1H), 9.70 (t, 1H), 8.45 (br. s, 3H), 8.37 (s, 1H), 8.05 (br. s, 3H),7.87 (s, 1H), 7.52 (d, 1H), 7.47 (d, 1H), 4.75 (s, 2H), 4.00 (d, 2H),3.86 (m, 1H), 3.32 (t, 2H), 3.12 (t, 2H), 2.79 (m, 2H), 2.25 (quintet,2H), 1.85 (m, 2H), 1.78 (m, 2H), 1.45 (m, 2H). MS m/e 420 (M+H)⁺.

Example 120 Preparation of 6a5,6,7,10-Tetrahydropyrrolo[3,4-c]carbazole-7(6H)-one

[1113] Prepared from 2-vinylindole (U. Pindur and M. Eitel, Helv. Chim.Acta, 1988, 71, 1060; M. Eitel and U. Pindur, Synthesis 1989, 364-367)by a procedure similar to that reported for synthesis of 1a. NMR(DMSO-d₆) δ12.10 (br. s, 1 H), 11.15 (br. s, 1H), 8.83 (d, 1H), 7.94 (m,2H), 7.60 (m, 2H), 7.32 (t, 1H). MS m/e 237 (M+H)⁺.

Example 121 Preparation of 6b8,9-Dimethyl-5,7-dihydropyrrolo[3,4-c]carbazole-5(6H),7(10H)-dione

[1114] 2-(But-2-en-2-yl)indole (87 mg, 0.51 mmol, prepared according toM. Eitel, and U. Pindur, Synthesis, 1989, 364-367) was mixed withmaleimide (97 mg, 1.0 mmol), and heated to 190-200° C. in a sealed tubefor 0.5 hr. The mixture was cooled to rt and the resulting solid waswashed with hot water (10×5 ml) to give the Diels-Alder adduct (91 mg,68%, MS m/e 267 (M−H)⁻). The adduct was dried in vacuo for 3 hrs andadded to the solution of DDQ (2.5 eq) in 5 ml of toluene. The dark brownsolution was stirred at 40° C. for 7 hrs and 20° C. overnight, thenevaporated to dryness. The residue was dissolved in EtOAc and washedwith saturated NaHCO₃ (5×5 ml), H₂O, saturated NaCl, and dried overMgSO₄. The crude product was triturated with EtOAc to afford 17 mg (28%)of the product as a yellow solid. ¹H NMR (DMSO-d₆) δ11.72 (s, 1H), 10.98(s, 1H), 8.76 (d, 1H), 7.54 (d, 1H), 7.48 (t, 1H), 7.23 (t, 1H), 2.69(s, 3H), 2.53 (s, 3H). MS m/e 263 (M−H)⁻.

Example 122 Preparation of 6e

[1115] This compound was prepared according to the same procedure for 1kusing, instead, 2a as starting material. Compound 6e is characterized asa yellow amorphous solid; R_(t) 6.77 min; ¹H-NMR (DMSO-d₆) δ12.60 (s,1H), 8.80 (s, 1H), 8.60 (broad, 3H), 8.00 (broad, 3H), 7.70 (d, 1H),7.60 (d, 1H), 5.00 (broad, 1H), 3.25 (m, 4H), 2.70 (broad, 2H), 2.25 (m,2H), 2.00-1.70 (a series of m, 6H). MS m/e 483 and 485 (M+2H for bromineisotopes).

Example 123 Preparation of 6f

[1116] This compound was prepared according to the same procedure as for1k using, instead, 2b as starting material. Compound 6f is characterizedas a yellow amorphous solid; R_(t) 7.13 min; ¹H-NMR (DMSO-d₆) δ12.60 (s,1H), 8.80 (s, 1H), 8.60 (broad, 3H), 8.00 (broad, 3H), 7.70 (dd, 2H),5.00 (broad, 1H), 3.25 (m, 4H), 2.70 (broad, 2H), 2.25 (m, 2H), 2.00 (2sets of broad, 2H), 1.50 (broad m, 4H). MS m/e 439 and 441 (M+2H, forchlorine isotopes).

Example 124 Preparation of 6g

[1117] This compound was prepared according to the same procedure as for1k using, instead, 2c as starting material. Compound 6g is characterizedas a yellow amorphous solid; R_(t) 6.72 min; ¹H-NMR (DMSO-d₆) δ12.50 (s,1H), 8.60 (broad, 3H), 8.50 (d, 1H), 8.00 (broad, 3H), 7.70 (m, 1H),7.50 (t, 1H), 5.00 (broad, 1H), 3.25 (m, 4H), 2.70 (broad, 2H), 2.25 (m,2H), 2.00 (2 sets of broad, 2H), 1.50 (broad m, 4H). MS m/e 423 (M+2H).

Example 125 Preparation of 6h6-Formyl-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one

[1118] POCl₃ (65.8 mg, 0.43 mmol) and DMF (200 uL, 2.59 mmol) werestirred for 30 min and added to5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-one (39mg, 0.15 mmol) suspended in DMF (200 uL). After stirring 1 hr at 20° C.and 1 hr at 60° C., 4 mL water was added. The precipitate (36 mg) wascollected and refluxed with acetone (40 mL). Evaporation of the filtrategave the product (18 mg, 42% yield) as a yellow-brown solid, mp>300° C.MS m/e 289 (M−H)⁻. NMR (DMSO-d₆) δ11.6 (br. s, 1H), 9.22 (s, 1H), 8.02(d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.24 (t, 1H), 5.20 (s, 2H).

Example 126 Preparation of 6i3-Bromo-11-L-lysyl-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-onedihydrochloride

[1119] The bis(t-butoxycarbonyl)-lysyl derivative was prepared from 5bas described for 1k, and purified by chromatography (CH₂Cl₂-EtOAc 75:25)to give an orange-yellow glass. The BOC groups were hydrolyzed bytreatment with 2M HCl in dioxane for 2.5 hr to afford the product as atan solid. R_(t) 8.43 min. MS m/e 469 and 471 (M+H)⁺, 341 and 343(M+H-Lysyl)⁺.

Example 127 Preparation of 6j3-Cyano-11-L-lysyl-5,7,8,9,10,11-hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-7(6H)-onedihydrochloride

[1120] The bis(t-butoxycarbonyl)-lysyl derivative was prepared from 5cas described for 1k. The BOC groups were hydrolyzed by treatment with 2MHCl in dioxane for 2.5 hr to afford the product. R_(t) 7.40 min. MS m/e416 (M+H)⁺, 310 (M+H-Lysyl)⁺.

Example 127a-127f

[1121] TABLE 14 Example Compound Mass Spec (m/e) 127a 6k 325 (M − H,+Na) 127b 61 275 (M − CH₂OH) 127c 6m 334 (M + H⁺) 127d 6n 290 (M − H)⁻127e 6o 321 (M − H) 127f 6p 364 (M + H)⁺

Example 128 Preparation of Precursor to 8b 2-(Cyclopenten-1-yl)pyrroleand 3-(Cyclopenten-1-yl)pyrrole

[1122] A modification of a previously reported procedure (M. Tashiro, Y.Yiru, and O. Tsuge, Heterocycles, 1974, 2, 575-584) was utilized.Pyrrole (20 g, 300 mmol) and the 1-(cyclopenten-1-yl)pyrrolidine (20 g,150 mmol, freshly prepared from cyclopentanone and pyrrolidine asdescribed (M. E. Kuehne, J. Amer. Chem. Soc. 1989, 81, 5400-5404) wereheated to 145° C. for 5 h. The volatile components were distilled off at40-45° C. and 12 mm Hg, then the product was kugelrohr distilled at100-140° C. and 1 mm Hg to afford 12.9 g (65%) of a 2:1 mixture of the2- and 3- isomers. Analytical samples were obtained by chromatography(hexanes-ether, 90:10 to 85:15).

[1123] 2-(Cyclopenten-1-yl)pyrrole: White solid (darkens in air), mp68-71° C. NMR (CDCl₃) δ8.24 (br. s, 1H), 6.74 (s, 1H), 6.21 (s, 1H),6.17 (s, 1H), 5.73 (s, 1H), 2.64 (t, 2H), 2.51 (t, 2H), 1.99 (quintet,2H). Anal. Calcd for C₉H₁₁N-0.2H₂O: C, 79.02 H, 8.40; N, 10.24. Found:C, 79.00; H, 8.12; N, 10.09.

[1124] 3-(Cyclopenten-1-yl)pyrrole: Light yellow oil (darkens rapidly inair). NMR (CDCl₃) δ8.10 (br. s, 1H), 6.74 (s, 2H), 6.37 (s, 1H), 5.82(s, 1H), 2.58 (t, 2H), 1.99 (quintet, 2H).

Example 129 Preparation of Precursors to 8b2-(Cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and3-(Cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole

[1125] Sodium hydride (7.0 g, 60% in mineral oil, 176 mmol) was rinsedwith hexane and suspended in ether (150 mL) and cooled to 0° C.Triisopropylsilyl chloride (23.3 g, 121 mmol), a 2:1 mixture of2-(cyclopenten-1-yl)pyrrole and 3-(cyclopenten-1-yl)pyrrole (3.0 g, 22.5mmol) and DMF (2 mL) were added. The mixture was stirred beneath areflux condenser. After hydrogen evolution subsided, the reaction wasstirred at 20° C. for 1 hr. The mixture was poured into ice-water,rinsed with water and saturated NaCl, dried, and concentrated to affordthe triisopropylsilyl derivatives (35.0 g, 104% crude yield). 2-Isomer:NMR (CDCl₃) δ6.83 (s, 1H), 6.26 (s, 1H), 6.19 (s, 1H), 5.70 (s, 1H),2.66 (t, 2H), 2.48 (t, 2H), 1.94 (quintet, 2H), 1.53 (m, 3H), 1.11 (d,18H). 3-Isomer NMR as reported in A. P. Kozikowski and X. -M. Cheng J.Org. Chem. 1984, 49, 3239-3240.

Example 130 Preparation of Precursor to 8b Dimethyl1-(triisopropylsilyl)-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate.

[1126] A 2:1 mixture of2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (6.2 g, 21.4 mmol) anddimethyl acetylenedicarboxylate (6.2 g, 43.7 mmol) were heated to 110°C. for 22 h. More dimethyl acetylenedicarboxylate (6.2 g, 43.7 mmol) wasadded and heating was continued for 6 more h. The resulting orange-brownoil was dissolved in ether (25 mL) then treated with hexanes (50 mL).The same process was repeated 3 more times on the precipitate. Thecombined ether-hexane soluble fractions were evaporated in vacuo, thenheated in vacuo to remove excess dimethyl acetylenedicarboxylate. Theresidue (3.3 g) was chromatographed (hexanes-ether 75:25) to give 490 mg(5.3% yield) product as a light orange oil. The same product wasobtained in 10% yield from pure2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole. NMR (CDCl₃) δ7.44 (d,1H), 7.05 (d, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.20 (t, 2H), 3.11 (t,3H), 2.09 (quintet, 2H), 1.70 (septet, 3H), 1.14 (d, 18H). MS m/e 430(M+H)⁺. Anal. Calcd for C₂₄H₃₅NO₄Si-0.5 H₂O: C, 65.71; H, 8.27; N, 3.19.Found: C, 65.51; H, 8.14; N, 2.83.

Example 131 Preparation of Precursor to 8b Diethyl1-(triisopropylsilyl)-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate

[1127] A 2:1 mixture of2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (1.16 g, 4.01 mmol)and diethyl fumarate (0.75 g, 4.36 mmol) were heated under nitrogen to150° C. for 64 h, affording the crude Diels-Alder adduct as an amberoil. The pure Diels-Alder adduct could be isolated by chromatography onsilica gel (hexanes-ether 90:10). NMR (CDCl₃) δ6.68 (d, 1H), 6.16 (d,1H), 4.20 (m, 4H), 3.95 (d, 1H), 2.91 (t, 2H), 2.49 (m, 1H), 2.09 (m,1H), 1.73 (m, 2H), 1.48 (septet, 3H), 1.30 (2t, 6H), 1.27 (d, 9H), 1.07(d, 9H). MS m/e 462 (M+H)⁺. DDQ (2.2 g, 9.7 mmol) was added in threeportions to a benzene solution (16 mL) of the crude Diels-Alder adductat 50° C. until no starting material remained (TLC and NMR). After 8 h,the mixture was filtered through Celite®. The precipitate was rinsedwith benzene, and the filtrate was evaporated to give 1.52 g of a blacksolid. This was chromatographed on silica gel (hexanes-ether 15:85 to20:80) to give the product (380 mg, 21% yield, 35% yield from 2-isomer)as a colorless oil. NMR (CDCl₃) δ7.42 (d, 1H), 7.05 (d, 1H), 4.40 (2q,4H), 3.20 (t, 2H), 3.12 (t, 2H), 2.17 (quintet, (septet, 3H), 1.39 (t,3H), 1.36 (t, 3H), 1.20 (d, 18H). MS m/e 458 (M+H)⁺.

Example 132 Preparation of Precursor to 8b1,6,7,8-Tetrahydrocyclopent[g]indole4,5-dicarboxylate

[1128] A mixture of diethyl1-(triisopropylsilyl)-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate(400 mg, 0.875 mmol) and 10 M NaOH (0.4 mL) in ethanol (5 mL) wasrefluxed under nitrogen for 3 h. The solvent was evaporated and thebrown residue dissolved in water and extracted three times with ether.The aqueous layer was acidified with HCl and extracted 3 times withEtOAc, and the combined organic extract was dried over MgSO₄ to give thecrude product (205 mg, 96%) as a brown solid, mp 311-312° C. NMR(DMSO-d₆) δ12.55 (br. s, 2H), 11.37 (s, 1H), 7.43 (d, 1H), 6.70 (d, 1H),3.08 (t, 2H), 3.02 (t, 2H), 2.14 (quintet, 2H). Anal. Calcd forC₁₃H₁₁NO₄: C, 63.67; H, 4.52; N, 5.71. Found: C, 63.15; H, 4.46; N,5.39. Hydrolysis of the dimethyl ester with NaOH in refluxing methanolfor 3 days afforded the same product.

Example 133 Preparation of Precursor to 8b1,6,7,8-Tetrahydrocyclopent[g]indole-4,5-dicarboxylic anhydride

[1129] A suspension of the diacid (184 mg) in acetic anhydride (3 mL)was heated to 73° C. for 1 h, then cooled to 0° C. The precipitate wascollected and washed with 2 mL ether to give the product as a yellowsolid (112 mg, 66%), mp 320° C. (sublimes). NMR (CD₃COCD₃) δ7.80 (d,1H), 6.94 (d, 1H), 3.30 (t, 2H), 3.24 (t, 2H), 2.38 (quintet, 2H).

Example 134 Preparation of Precursor to 8b Diethyl1-(triisopropylsilyl)-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate

[1130] A 2:1 mixture of2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (1.16 g, 4.01 mmol)and diethyl fumarate (0.75 g, 4.36 mmol) was heated under nitrogen to150° C. for 64 h, affording the crude Diels-Alder adduct as an amberoil. The pure Diels-Alder adduct could be isolated by chromatography onsilica gel (hexanes-ether 90:10). NMR (CDCl₃) δ6.68 (d, 1H), 6.16 (d,1H), 4.20 (m, 4H), 3.95 (d, 1H), 2.91 (t, 2H), 2.49 (m, 1H), 2.09 (m,1H), 1.73 (m, 2H), 1.48 (septet, 3H), 1.30 (2t, 6H), 1.27 (d, 9H), 1.07(d, 9H). MS m/e 462 (M+H)⁺. DDQ (2.2 g, 9.7 mmol) was added in threeportions to a benzene solution (16 mL) of the crude Diels-Alder adductat 50° C. until no starting material remained (TLC and NMR). After 8 h,the mixture was filtered through Celite®. The precipitate was rinsedwith benzene, and the filtrate was evaporated to give 1.52 g of a blacksolid. This was chromatographed on silica gel (hexanes-ether 15:85 to20:80) to give the product (380 mg, 21% yield, 35% yield from 2-isomer)as a colorless oil. NMR (CDCl₃) δ7.42 (d, 1H), 7.05 (d, 1H), 4.40 (2q,4H), 3.20 (t, 2H), 3.12 (t, 2H), 2.17 (quintet, 2H), 1.67 (septet, 3H),1.39 (t, 3H), 1.36 (t, 3H), 1.20 (d, 18H). MS m/e 458 (M+H)⁺.

Example 135 Preparation of Precursor to 8b1,6,7,8-Tetrahydrocyclopent[g]indole-4,5-dicarboxylate

[1131] A mixture of diethyl1-(triisopropylsilyl)-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate(400 mg, 0.875 mmol) and 10 M NaOH (0.4 mL) in ethanol (5 mL) wasrefluxed under nitrogen for 3 h. The solvent was evaporated and thebrown residue dissolved in water and extracted three times with ether.The aqueous layer was acidified with HCl and extracted 3 times withEtOAc, and the combined organic extract was dried over MgSO₄ to give thecrude product (205 mg, 96%) as a brown solid, mp 311-312° C. NMR(DMSO-d₆) δ12.55 (br. s, 2H), 11.37 (s, 1H), 7.43 (d, 1H), 6.70 (d, 1H),3.08 (t, 2H), 3.02 (t, 2H), 2.14 (quintet, 2H). Anal. Calcd forC₁₃H₁₁NO₄: C, 63.67; H, 4.52 N, 5.71. Found: C, 63.15; H, 4.46; N, 5.39.Hydrolysis of the dimethyl ester with NaOH in refluxing methanol for 3days afforded the same product.

Example 136 Preparation of 8b1,6,7,8-Tetrahydrocyclopent[g]indole-4,5-dicarboxylate imide

[1132] A mixture of hexamethyldisilazane (1.38 mL, 1.06 g, 6.56 mmol)and methanol (0.135 mL, 107 mg, 3.33 mmol) was added to1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylic anhydridedissolved in DMF (3 mL). The mixture was heated to 73° C. for 4 h, thencooled. The solvent was evaporated and the residue was stirred withdilute HCl. The precipitate was collected and washed with EtOAC to givethe product (132 mg, 88% yield) as a yellow solid, mp>350° C. NMR(DMSO-d₆) δ11.81 (br. s, 1H), 10.71 (br. s, 1H), 7.67 (d, 1H), 6.75 (d,1H), 3.18 (t, 2H), 3.10 (t, 2H), 2.22 (quintet, 2H). MS m/e 225 (M−H)⁻.Anal. Calcd for C₁₃H₁₀N₂O₂-0.2H₂O: C, 67.94; H, 4.46; N, 12.19. Found:C, 67.81; H, 4.50, N, 12.04.

Example 137 Preparation of 8c3-Bromo-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate imide

[1133] Pyridinium bromide perbromide (60 mg, 0.187 mmol) was added to asuspension of 1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylateimide (40 mg, 0.177 mmol) in DMF (0.9 mL). Water (3.5 mL) was addedafter 50 min. The precipitate was collected, rinsed with water, anddried to give the product (54 mg, 100% yield) as a yellow solid, mp>350°C. NMR (DMSO-d₆) δ12.18 (br. s, 1H), 10.71 (br. s, 1H), 7.83 (d, 1H),3.18 (t, 2H), 3.10 (t, 2H), 2.22 (quintet, 2H). MS m/e 303 and 305(M−H)⁻. Anal. Calcd. for C₁₃H₉N₂O₂Br: C, 51.17; H, 2.97; N, 9.18; Br,26.19. Found: C, 50.91; H, 3.19; N, 8.99; Br, 26.40.

Example 138 Preparation of 8d3-Cyano-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate imide

[1134] A mixture of3-bromo-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate imide (36mg) and CuCN (31 mg) in DMF (0.4 mL) was heated to 155° C. for 4 hr,cooled to 20° C. The grey precipitate containing product and coppersalts was chromatographed on silica gel (2×0.5 cm) with DMF. Theevaporated eluent was boiled with water for 5 min, and the goldenprecipitate was collected. Yield 8 mg, 27%. mp>350° C. ¹H NMR (DMSO-d₆)δ12.86 (br s, 1H), 10.94 (s, 1H), 8.55 (s, 1H), 3.17 (m, 4H), 2.24(quintet, 2H). MS m/e 250 (M−H)⁻. Additional product eluted with DMSO.Anal. Calcd. for C₁₄H₉N₃O₂1.2 H₂O: C, 61.63; H, 4.21; N, 15.40. Found:C, 61.33; H. 3.60; N, 14.93.

Example 139 Preparation of 8e1,6,7,8-Tetrahydrocyclopent[g]indole-4,5-dicarboxylate hydrazide

[1135] Dimethyl1-(triisopropylsilyl)-1,6,7,8-tetrahydrocyclopent[g]indole-4,5-dicarboxylate(34 mg, 0.079 mmol) and hydrazine hydrate (83 mg, 1.23 mmol) wererefluxed in ethanol (0.6 mL) for 24 h. After evaporation of solvent, theresidue was suspended in EtOAc rinsed with water, 1 M HCl, and saturatedNaCl, then dried. The solvent was evaporated and the residue wassuspended in chloroform, affording a precipitate of the product (2 mg,10% yield), mp>250° C. NMR (acetone-d₆) δ7.56 (d, 1H), 7.50 (d, 1H),3.60 (t, 2H), 3.19 (t, 3H), 2.86 (br s. 2H), 2.23 (quintet, 2H). MS m/e242 (M+H)⁺.

Example 139a-139b Data for 8f-8 g

[1136] TABLE 15 Example Compound Mass Spec (m/e) 139a 8f 383, 385, 387(M − H)⁻ 139b 8g 250 (M − H)

Example 139c Preparation of 8h

[1137] 2-(1-cyclopentenyl)-1-azaindole (500 mg; 2.72 mmol), maleimide(527 mg; 5.44 mmol) and YbBr₃ (113 mg) in toluene (10 mL) were stirredat reflux under nitrogen for 1.5 hours. After cooling to roomtemperature the product was collected, washed with methanol and dried togive 420 mg (55%). MS m/e 380 (M-1). The tetrahydrocarbazoleintermediate (20 mg, 0.07 mmol) was suspended in acetic acid, DDQ (80mg, 0.36 mmol) added and the mixture maintained at 55° C. for 12 hours.The solvent was removed at reduced pressure, the residue triturated withMeOH and the product collected to give 16 mg (84%) of 8 h as a reddishsolid. ¹H-NMR (DMSO-d₆) δ12.50 (s, 1H), 11.02 (s, 1H), 9.0 (m, 1H), 8.55(m, 1H), 7.35 (m, 1H), 3.21 (m, 4H), 2.28 (broad m, 2H). MS m/e 276(M−H).

Example 139d Preparation of 8i

[1138] Compound 8h (200 mg) and CH₃I (2 mL) in DMF (10 mL) was heated ina sealed reaction tube at 110° C. for 3 hours. After cooling the mixtureto room temperature, the product was precipitated with the addition ofEt₂O, collected and dried to give 8i 300 mg (100%). MS m/e 294 (M+H).

Example 139e Preparation of 8j

[1139] A solution of example 1 (100 mg, 0.36 mmol) in THF (10 mL) wasadded BH₃-THF (1 mL of 1 mol solution) followed by heating for 2 hoursat 60° C. An additional 2 ml BH₃THF was added and heating continued for12 hours. The solution was concentrated at reduced pressure to a solid.2N HCl was added to the residue and stirred for 2 hours. The product wascollected and dried to give 35 mgs (39%) of a white solid. MS m/e 249(M+H).

Example 139f Preparation of 8k

[1140] 8k was prepared in a manner similar to that described in Example139c to give the title compound. MS m/e 301 (M+H).

Example 140 Preparation of Precursor to 11a Ethyl4-Cyano-1,2,3,10-tetrahydrocyclopenta[a]carbazole-5-carboxylate

[1141] DDQ (39 mg, 0.17 mmol, 220 mol %) was added to solution of ethyl4-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate (24mg, 0.078 mmol) in toluene (12 mL). The solution immediately turned darkbrown, and was stirred at 20° C. for 1.5 hr. The solvent was evaporated.The residue was dissolved in EtOAc and rinsed with dilute aqueousascorbic acid and twice with saturated NaHCO₃. Evaporation of thesolvent afforded crude product (21 mg) which was recrystallized fromEtOAc gave the product (9 mg, 38% yield) as a beige solid, mp 229-231°C. NMR (CDCl₃) δ8.28 (s, 1H), 7.49 (s, 2H), 7.26 (s, 2H), 4.64 (q, 2H),3.30 (t, 2H), 3.20 (t, 2H), 2.36 (quintet, 2H), 1.54 (t, 3H).

Example 141 Preparation of 11a5,7,8,9,10,11-Hexahydrocyclopent[a]pyrrolo[3,4-c]carbazole-5(6H)-one

[1142] Ethyl4-Cyano-1,2,3,10-tetrahydrocyclopenta[a]carbazole-5-carboxylate (14 mg)in DMF (1.6 mL) was hydrogenated at 55 psi over W2 Raney nickel (150 mg)for 2.5 days. The catalyst was removed by filtration and the DMF wasevaporated in vacuo to give the product (12 mg, 100% yield) as lightbrown crystals. A sample was recrystallized from DMF, boiled withethanol, cooled, and filtered to give the product as an off-white solid,mp>300° C. NMR (DMSO-d₆) δ11.45 (s, 1H), 9.06 (d, 1H), 8.47 (s, 1H),7.51 (d, 1H), 7.40 (t, 1H), 7.16 (t, 1H), 4.41 (s, 2H), 3.21 (t, 2H),3.04 (t, 2H), 2.30 (quintet, 2H). Anal. Calcd for C₁₇H₁₄N₂O: C, 77.84;H, 5.38; N, 10.68. Found: C, 77.40; H, 5.66; N, 10.49.

Example 142 Preparation of 11b5,7,9,10,11,12-Hexahydrocyclohexano[a]pyrrolo[3,4-c]carbazole-5(6H),7(8H)-dione

[1143] Prepared from 2-(cyclohexen-1-yl)indole by a procedure similar tothat reported for synthesis of 5a. NMR (DMSO-d₆) δ11.73 (br. s, 1H),10.90 (br. s, 1H), 8.77 (d, 1H), 7.58 (d, 1H), 7.51 (t, 1H), 7.27 (t,1H), 3.22 (t, 2H), 3.03 (t, 2H), 1.90 (m, 2H). MS m/e 289 (M−H)⁻.

Example 143 Preparation of 11c9-Ethyl-8-propyl-5,7-dihydropyrrolo[3,4-c]carbazole-5(6H),7(10H)-dione

[1144] Prepared from 2-(hept-3-en-3-yl)indole according to the generalprocedure described for synthesis of8,9-dimethyl-5,6,7,10-tetrahydropyrrolo[3,4-c]carbazole-7(6H)-one.Purified by preparative TLC (10% MeOH in CH₂Cl₂) to afford 38 mg (40%)of product. ¹H NMR (CDCl₃) δ11.77 (s, 1H), 10.91 (s, 1H), 8.77 (d, 1H),7.58 (m, 2H 7.25 (m, 1H), 3.10-3.30 (m, 4H), 1.56 (m, 2H), 1.05 (t, 3H),1.16 (t, 3H). MS m/e 305 (M−H)⁻.

Example 144 Preparation of 11d

[1145] Compound 11d was prepared from 2-(cyclohexen-1-yl)-1-methylindoleby a procedure similar to that reported for the synthesis of 1a; mp 242°C. MS m/e 303 (M−H)^(−.)

Example 145 Preparation of 11f5,7,10,11-Tetrahydrofuran[a-3,2]pyrrolo[3,4-c]carbazole-5(6H),7(9H)-dione

[1146] Prepared from 2-(2,3-dihydrofuran-4-yl)indole according to thegeneral procedure described for synthesis of8,9-dimethyl-5,6,7,10-tetrahydropyrrolo[3,4-c]carbazole-7(6H)-one.Purified by preparative TLC (10% MeOH in CH₂Cl₂) to afford 0.15 mg (˜1%)of product. ¹H NMR (CD₃COCD₃) δ9.08 (d, 1H), 7.68 (d, 1H), 7.48 (t, 1H),7.26 (t, 1H), 3.58 (m, 2H), 2.30 m, 2H). MS m/e 277 (M−H)⁻.

Example 146 Preparation of 11g 5,7-Dihydrofuran[a-3,2]pyrrolo[3,4-c]carbazole-5(6H),7(11H)-dione

[1147] Prepared from 2-(furan-3-yl)indole according to the generalprocedure described for synthesis of8,9-dimethyl-5,6,7,10-tetrahydropyrrolo[3,4-c]carbazole-7(6H)-one.Purified by preparative TLC (10% MeOH in CH₂Cl₂) to afford 0.57 mg (˜1%)of the product. ¹H NMR (DMSO-d₆) δ12.0 (s, 1H), 10.9 (s, 1H), 8.9 (d,1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 7.58 (t, 1H), 7.26 (t, 1H).MS m/e 275 (M−H)⁻.

Example 147 Preparation of 12a

[1148] To a solution of indole (10.72 g, 92.5 mmol) in THF (400 mL) at−78° C. was added 2.0 M n-BuLi (48.0 mL, 96 mmol). After stirring for 25min, CO₂ was bubbled through the solution for 12 min. The mixture waswarmed to RT, and solvent (and excess CO₂) was reduced by 50% by rotaryevaporation. Additional THF (200 mL) was added, and the solution cooledto −78° C. before adding 1.7 M t-BuLi (54 mL, 91.8 mL). After stirringfor 2 h, a solution of benzyl 4-oxo-1-piperidinecarboxylate (23.3 g,99.9 mmol) in THF (30 mL) was added. After 1 h, the reaction wasquenched with water (10 mL) and poured into a 10% aqueous solution ofNH₄Cl (200 mL). The mixture was extracted into EtOAc, and the organiclayer was separated and washed with brine. After drying over MgSO₄,filtration followed by rotary evaporation afforded a solid that wastriturated with ether (3×25 mL) and yielded the corresponding alcohol(18.5 g, 57%).

[1149] To a solution of the above adduct (11.2 g, 32.0 mmol) in acetone(300 mL) was added 2 N HCl (2.0 mL). After stirring for 3 h, more 2 NHCl (1 mL) was added. After 1 h, a saturated aqueous solution of NaHCO₃was added and solvent was reduced by rotary evaporation. The residue wasextracted into CH₂Cl₂, washed with water and dried over Na₂SO₄. Afterfiltration, solvent was removed by rotary evaporation, and the residuewas triturated with ether to afford the corresponding diene as a whitesolid (9.5 g, 89%).

[1150] A mixture of the above diene (1.02 g, 3.1 mmol) and maleimide(0.59 g, 6.1 mmol) in xylenes (20 mL) was heated to reflux for 18 h. Thecooled mixture was filtered and the solid was successively washed withwater (3×20 mL), ether (3×5 mL) and more water (3×10 mL). After dryingunder vacuum afforded the cycloadduct 1.35 g (100%).

[1151] A mixture of the above cycloadduct (325 mg, 0.76 mmol) and 10% Pdon carbon (375 mg) in di(ethylene glycol) diethyl ether (10 mL) washeated to reflux for 3 h. The cooled mixture was filtered through a plugof celite and the filter cake was washed with DMF (3×15 ml). Thefiltrate was evaporated to dryness and the resulting residue trituratedwith ether to afford the title compound (175 mg, 81%) as a pale greenpowder. ¹H NMR (DMSO-d₆) δ13.2 (s, 1H), 11.32 (s, 1H), 10.19 (s, 1H),8.92 (d, J=7.9, 1H), 8.81 (d, J=5.8, 1H), 8.51 (d, J=5.8, 1H), 7.78 (d,J=7.9, 1H), 7.60 (app. t, J=7.3, 1H), 7.41 (app t, J=7.3, 1H). MS m/e288 (M+H)⁺.

Example 148 Preparation of 12b

[1152] A mixture of imide 12a (28.5 mg, 0.10 mmol), Sn powder (31.2 mg,0.26 mmol), HOAc (4 ml), and conc. HCl (2 ml) was heated to reflux. MoreSn was added after 20 h (42.5 mg, 0.35 mmol) and 26 h (65.0 mg, 55mmol). The solution was decanted and the metallic residue was rinsedwith DMF. The supernatent was evaporated and triturated with aqueousNaHCO₃ and water. The resulting solid was slurried in DMSO and filtered.The filtrate was extracted into EtOAc and washed with water (3×10 mL)and dried over MgSO₄. After filtration, solvent was removed by rotaryevaporation, and the residue was triturated with ether to yield amixture of lactams (1.1 mg, 4%). NMR (DMSO-d₆) δ13.0 (br s, 1H), 10.4(s, 0.65H), 10.13 (s, 0.35H), 8.88 (d, 0.35H), 8.70 (m, 1.65H), 8.51 (d,0.35H), 8.44 (d, 0.65H), 8.27 (d, 0.35H), 8.11 (d, 0.65H), 7.76 (m, 1H).7.53 (m, 1H), 7.34 (m, 1H), 4.97 (s, 2H). MS m/e 274 (M+H)⁺.

Example 149 Preparation of 12c

[1153] To a mixture of hydroxylactam 12d (5.2 mg, 0.018 mmol) in CH₂Cl₂(4 mL) was added Et₃SIH (123 uL) and TFA (297 uL). The mixture wasstirred for 20 h, and solvent was removed by repeated rotary evaporationfrom iPrOH. Trituration with ether afforded the lactam product (2.3 mg,45%). NMR (DMSO-d₆) δ12.90 (s, 1H), 10.40 (s, 1H), 8.70 (m, 2H), 8.44(d, j=5.65, 1H), 8.11 (d, J=7.8, 1H), 7.76 (d, J=8.3, 1H), 7.53 (m, 1H),7.34 (m, 1H), 4.97 (s, 2H). MS m/e 274 (M+H)⁺.

Example 150 Preparation of 12d

[1154] To a mixture of imidel2a (28.5 mg, 0.10 mmol) in acetone (7 mL)was added iPrI (200 uL). After stirring overnight, solvent was removedby rotary evaporation, and the residue was taken up in MeOH (10 mL) andtreated with NaBH₄ (22.4 mg, 0.59 mmol). After stirring overnight, thereaction was quenched with 1 N HCl (5 mL) and warmed to 50° C. Themixture was neutralized with aqueous NaHCO₃, extracted into EtOAc,washed successively with water and brine and dried over MgSO₄. Afterfiltration, solvent was removed by rotary evaporation, and the residuewas purified by preparative HPLC with 25% MeCN/H₂O containing 0.1% TFAto afford the product hydroxylactam (7.0 mg, 25%). ¹³C NMR (DMSO-d₆)δ170.5, 148.6, 145.3, 144.0, 140.1, 136.6, 126.7, 124.5, 123.8, 121.9,121.0, 117.4, 116.1, 116.0, 115.8, 112.4, 78.3. ¹H NMR (DMSO-d₆) δ12.90(s, 1H), 10.37 (s, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.37(d, J=7.9, 1H), 7.73 (d, J=8.2, 1H), 7.52 (app. t, J=7.4, 1H), 7.33 (appt, J=7.4, 1H), 6.63 (d, J=10.0, 1H), 6.40 (d, J=10.0, 1H). MS m/e 290(M+H)⁺ and m/e 273 (M−OH)⁺.

Example 151 Preparation of 12e

[1155] To a mixture of imide 12a (50.1 mg, 0.17 mmol) in MeCN (5.0 mL)was added ethyl acrylate (50 uL) and DBU (50 uL). The reaction waswarmed to reflux for 20 h, cooled and diluted with water (10 mL). Thesolid product was collected by filtration and washed with 50% aqueousEtOH (2×5 mL) and 95% EtOH (3×1 mL) and dried under vacuum (32 mg, 49%).¹³C NMR (DMSO-d₆) δ171.1, 169.3, 168.8, 149.2, 145.3, 140.7, 138.7,129.2, 128.1, 125.6, 124.7, 121.8, 121.2, 121.0, 118.3, 116.2, 114.6,112.8, 60.7, 34.0, 33.2, 14.4. ¹H NMR (DMSO-d₆) δ13.19 (s, 1H), 10.10(s, 1H), 8.83 (d, J=8.0, 1H), 8.76 (d, J=5.8, 1H), 8.42 (d, J=5.8, 1H),7.73 (d, J=8.0, 1H), 7.59 (app. t, J=7.2, 1H), 7.39 (app t, J=7.2, 1H),4.00 (q, J=7.1, 2H), 3.88 (t, J=7.0, 2H), 2.73 (t, J=7.0, 2H), 1.07 (t,J=7.1, 3H). MS m/e 388 (M+H)⁺.

Example 152 Preparation of 12f

[1156] To a solution of imide 12a (28.9 mg, 0.1 mmol) in DMF (2.0 mL)was added NaH (60%, 5.1 mg, 0.13 mmol). After stirring for 15 min.,(3-bromopropoxy)-t-butyldimethylsilane (30 uL) was added and thereaction was warmed to 50° C. for 2 h. The solution was cooled, pouredinto 10% aqueous NH₄Cl (10 mL) and extracted into EtOAc. The organiclayer was separated and washed successively with water, aqueous NaHCO₃and brine, and dried over Na₂SO₄. After filtration, solvent was removedby rotary evaporation, and the residue was taken up in MeOH (10 mL) andtreated with AcCl (90 uL). After 1 h, solvent was removed by rotaryevaporation and the product residue was triturated with ether (2×1 mL)and dried under vacuum (21.7 mg, 57%). ¹H (DMSO-d₆) δ13.54 (s, 1H),10.16 (s, 1H), 8.89 (d, J=9.5, 1H), 8.84 (d, J=6.7, 1H), 8.71 (d, J=6.7,1H), 7.77 (d, 8.2, 1H), 7.63 (app. t, J=7.2, 1H), 7.43 (app t, J=7.2,1H), 5.00 (m, 1H), 3.72 (t, J=7.0, 2H), 3.48 (d, J=7.0, 2H), 1.82 (p,J=7.4, 2H). MS m/e 404 (M+Na)⁺.

Example 153 Preparation of 12g

[1157] To a solution of imide 12a (28.9 mg, 0.1 mmol) in DMF (2.0 mL)was added NaH (60%, 5.1 mg, 0.13 mmol). After stirring for 15 min.,(3-bromoethoxy)-t-butyldimethylsilane (30 uL) was added and the reactionwas warmed to 50° C. for 2 h. The solution was cooled, poured into 10%aqueous NH₄Cl (10 mL) and extracted into EtOAc. The organic layer wasseparated and washed successively with water, aqueous NaHCO₃ and brineand dried over Na₂SO₄. After filtration, solvent was removed by rotaryevaporation, and the residue was taken up in MeOH (10 mL) and treatedwith AcCl (90 uL). After 1 h, solvent was removed by rotary evaporationand the product residue was triturated with ether (2×1 mL) and driedunder vacuum (6.5 mg, 20%). ¹H (DMSO-d₆) δ13.51 (s, 1H), 10.21 (s, 1H),8.93 (d, J=8.8, 1H), 8.81 (d, J=5.7, 1H), 8.52 (d, J=5.7, 1H), 7.79 (d,8.8, 1H), 7.62 (app. t, J=7.2, 1H), 7.43 (app t, J=7.2, 1H), 4.87 (m,1H), 3.75 (m, 2H), 3.67 (m, 2H).MS m/e 332 (M+H)⁺.

Example 154 Preparation of 12h

[1158] To a solution of imide 12a (28.7 mg, 0.1 mmol) in DMF (2.0 mL)was added NaH (60%, 5.2 mg, 0.13 mmol). After stirring for 15 min.,ethyl bromoacetate (14 uL) was added and the reaction was warmed to 60°C. for 1 h. More NaH (5.8 mg) was added followed by more ethylbromoacetate (15 uL). This mixture was stirred at 60° C. for 1 h. Thesolution was cooled, poured into 10% aqueous NH₄Cl (10 mL) and extractedinto EtOAc. The organic layer was separated and washed successively withwater, aqueous NaHCO₃ and brine and dried over Na₂SO₄. After filtration,solvent was removed by rotary evaporation, and the residue wastriturated with MeOH (2×1 mL). The product was dried under vacuum (18.2mg, 48%). ¹H (DMSO-d₆) δ13.35 (s, 1H), 10.16 (s, 1H), 8.83 (m, 2H), 8.52(d, J=5.9, 1H), 7.79 (d, J=8.2, 1H), 7.63 (app. t, J=8.2, 1H), 7.43 (appt, J=8.2, 1H), 4.51 (s, 2H), 4.14 (q, J=7.1, 2H), 1.20 (t, J=7.1, 3H).MS m/e 374 (M+H)⁺.

Example 155 Preparation of 12i

[1159] To a solution of imide 12a (28.7 mg, 0.1 mmol) in DMF (2.0 mL)was added NaH (60%, 12.8 mg, 0.32 mmol). After stirring for 15 min.,2-picolyl chloride hydrochloride (19.6 mg, 0.12 mmol) was added and thereaction was warmed to 65° C. for 3 h. The solution was cooled, pouredinto 10% aqueous NH₄Cl (10 mL) and the product was collected byfiltration. After washing with water (5 mL) and MeOH (2×1 mL), theproduct was dried under vacuum (20.5 mg, 54%). ¹H (DMSO-d₆) δ13.38 (s,1H), 10.12 (s, 1H), 8.87-8.80 (m, 2H), 8.50 (s, 1H), 8.41 (s, 1H), 7.76(m, 2H), 7.61 (app. t, J=7.4, 1H), 7.47 (d, J=7.7, 1H), 7.39 (app t,J=7.4, 1H), 7.25 (app t, J=5.4), 4.99 (s, 2H). MS m/e 379 (M+H)⁺.

Example 156 Preparation of 12j

[1160] To a solution of ester 12e (2.1 mg, 0.005 mmol) in EtOH (4.0 mL)was added 1 N NaOH (300 uL), and the mixture was warmed to 70° C. for0.5 h. After the reaction was cooled, solvent was removed by rotaryevaporation. The residue was taken up in water (1 mL) and acidified topH 3 with 1 N aqueous HCl. Solvent was removed by rotary evaporation andthe residue triturated with water. The product was dried under vacuum(1.1 mg, 56%). ¹H (DMSO-d₆) δ12.78 (s, 1H), 9.35 (s, 1H), 8.78-8.53 (m,2H), 8.39 (d, J=5.5, 1H), 8.14 (d, J=7.9, 1H), 7.70 (d, J=7.9, 1H), 7.49(app. t, J=7.8, 1H), 7.25 (app t, J=7.8, 1H), 3.54 (t, J=,2H), 2.57 (t,J=7.1, 2H). MS m/e 360 (M+H)⁺.

Example 157 Preparation of 12k

[1161] To a mixture of imide 12a (28.9 mg, 0.1 mmol) in MeCN (5.0 mL)was added acrylonitrile (50 uL) and DBU (5 uL). The reaction was warmedto reflux for 15 h, cooled and diluted with water (10 mL). The solidproduct was collected by filtration and washed with 50% aqueous EtOH(2×5 mL) and 95% EtOH (3×1 mL). The filtrate was evaporated andtriturated with water (2×1 mL) and ether (2×1 mL) and dried under vacuum(4.0 mg, 12%). ¹H NMR (DMSO-d₆) δ13.3 (s, 1H), 10.20 (s, 1H), 8.93 (d,J=7.9, 1H), 8.83 (d, J=5.8, 1H), 8.53 (d, J=5.8, 1H), 7.80 (d, J=7.9,1H), 7.63 (app. t, J=7.2, 1H), 7.44 (app t, J=7.2, 1H), 3.97 (t, J=7.1,2H), 3.00 (t, J=7.0, 2H). MS m/e 341 (M+H)⁺.

Example 158 Preparations of 12l and 12m

[1162] To a solution of the imide from example 12a (28.6 mg, 0.1 mmol)in DMF (2.0 mL) was added NaH (60%, 5.0 mg, 0.13 mmol). After stirringfor 15 min., p-(t-butyldimethylsiloxy)benzyl chloride (29.7 mg) wasadded and the reaction was warmed to 60° C. for 4 h. The solution wascooled, poured into water (5 mL) and filtered. The solid was taken up inMeOH (10 mL) and treated with AcCl (50 uL). After 1 h, solvent wasremoved by rotary evaporation and the residue triturated with MeOH (2×1mL) to afford the mono-alkylated product (12I) that was dried undervacuum (8.9 mg, 23%). ¹H (DMSO-d₆) δ13.24 (s, 1H), 10.16 (s, 1H), 9.37(s, 1H), 8.88 (d, J=8.0, 1H), 8.78 (s, 1H), 8.47 (d, J=5.7, 1H), 7.75(d, J=8.2, 1H), 7.60 (app. t, J=7.8, 1H), 7.40 (app t, J=7.8, 1H), 7.21(d, J=8.2, 2H), 6.69 (d, J=8.2, 2H), 4.72 (s, 2H). Evaporation of theMeOH washings left a residue that was fractionated by preparative HPLC(45% MeCN/H₂O w/0.1% TFA) to afford the di-alkylated product (12m, 8.2mg, 16%). ¹H (DMSO-d₆) δ10.28 (s, 1H), 9.36 (s, 2H), 9.14 (d, J=8.0,1H), 8.63 (s, 1H), 8.35 (d, J=5.7, 1H), 7.93 (d, J=8.4, 1H), 7.66 (app.t, J=7.4, 1H), 7.49 (app t, J=7.4, 1H), 7.22 (d, J=8.2, 2H), 6.83 (d,J=8.2, 2H), 6.69 (d, J=8.2, 2H), 6.61 (d, J=8.2, 2H), 6.15, (s, 2H),4.75 (s, 2H).

Example 159 Preparation of 12n

[1163] The procedure described for 12a was repeated with 5-methylindolein place of indole. ¹³C NMR (DMSO-d₆) δ171.3, 170.6, 149.3, 145.1,139.0, 138.8, 130.6, 130.2, 129.4, 125.8, 124.4, 121.6, 121.1, 119.3,116.2, 114.2, 112.3,21.6. ¹H NMR (DMSO-d₆) δ13.07 (s, 1H), 11.27 (s,1H), 10.12 (s, 1H), 8.75 (d, J=5.8, 1H), 8.63 (s, 1H), 8.44 (d, J=5.8,1H), 7.61 (d, J=8.3, 1H), 7.39 (d, J=8.3, 1H), 2.50 (s, 3H).

Example 160 Preparation of 12o

[1164] The synthesis described for 12a was performed with 7-methylindolein place of indole for the preparation of 12o. ¹H NMR (DMSO-d₆) δ12.37(s, 1H), 11.18 (s, 1H), 10.04 (s, 1H), 8.69 (d, J=5.7, 1H), 8.63-8.50(m, 2H), 7.29 (d, J=6.9, 1H), 7.20 (ap t, J=7.6, 1H), 2.53 (s, 3H). MSm/e 302 (M+H)⁺.

Example 161 Preparation of 12p

[1165] To a mixture of imide 12a (496 mg, 1.73 mmol) in DMF (30 mL) wasadded NBS (341 mg, 192 mmol), and the reaction was warmed to 60° C. for2 h. More NBS (85 mg, 0.48 mmol) was added, and heating was continuedfor 1 h. More NBS (25 mg, 0.14 mmol) was added, and heating wascontinued for 1 h. The reaction mixture was cooled, and solvent wasremoved by rotary evaporation. The residue was triturated with 95% EtOH(3×10 mL) and dried under vacuum (479 mg, 76%). ¹H NMR (DMSO-d₆) δ13.25(s, 1H), 11.33 (s, 1H), 10.08 (s, 1H), 8.88 (s, 1H), 8.77 (d, J=5.6,1H), 8.38 (d, J=5.6, 1H), 7.64 (s, 2H).

Example 162 Preparation of 12q

[1166] A mixture of bromide compound 12p (17.1 mg, 0.047 mmol),PdCl₂(PPh₃)₂ (3.2 mg, 0.005 mmol), NaOAc (22.5 mg), and methoxyethanol(2 mL) was purged with CO and warmed to 150° C. for 2 h The reactionmixture was cooled, filtered through a pad of celite with the aid ofMeOH (3×1 mL), and the filtrate was reduced by rotary evaporation. Theresidue was triturated with water (3×10 mL), dried under vacuum, andpurified by preparative HPLC (30% MeCN/H₂O w/ 0.1% TFA, 3.1 mg, 17%) ¹HNMR (DMSO-d₆) δ13.77 (s, 1H), 11.41 (s, 1H), 10.18 (s, 1H), 9.66 (s,1H), 8.88 (d, J=5.6, 1H), 8.67 (d, J=5.6, 1H), 8.21 (d, J=7.5, 1H), 7.88(d, J=7.4, 2H), 4.44 (m, 2H), 3.65 (m, 2H), 3.34 (s, 3H). MS m/e 390(M+H)⁺.

Example 163 Preparation of 12r

[1167] To a mixture of imide compound 12q (20.1 mg, 0.052 mmol), in THF(2 mL) was added a 2M solution of LiBH₄ in THF (200 uL). After 2 h, thereaction mixture was quenched with MeOH, then water, then 1 N HCl (5drops). This mixture was neutralized with a solution of aqueous NaHCO₃and extracted into EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, and solvent was removed by rotary evaporation. The residuewas purified by preparative HPLC (25% MeCN/H₂O w/ 0.1% TFA, 2.0 mg, 10%)¹H NMR (DMSO-d₆) δ13.18 (s, 1H), 10.39 (s, 1H), 8.90 (s, 1H), 8.85 (s,1H), 8.60 (d, J=5.6, 1H), 8.32 (d, J=5.6, 1H), 7.97 (d, J=7.5, 1H), 7.68(d, J=7.4, 2H), 6.44 (d, J=6.5, 1H), 6.33 (d, J=6.5, 1H), 4.30 (m, 2H),3.51 (m, 2H), 3.16 (s, 3H). MS m/e 392 (M+H)⁺.

Example 164 Preparation of 12s

[1168] A mixture of bromide compound 12p (21.2 mg, 0.058 mmol),PdCl₂(PPh₃)₂ (4.6 mg, 0.007 mmol), 2-(tributylstannyl)thiophene (75 uL)and DMF (2 uL) was warmed to 100° C. for 20 h. The reaction mixture wascooled, filtered through a pad of celite with the aid of DMF (3×1 mL)and the filtrate was reduced by rotary evaporation. The residue wastriturated with ether (3×3 mL), and pentane (10×2 mL) and dried undervacuum (8.1 mg, 38%) ¹H NMR (DMSO-d₆) δ13.26 (s, 1H), 11.43 (s, 1H),10.16 (s, 1H), 9.16 (s, 1H), 8.80 (d, J=5.7, 1H), 8.47 (d, J=5.7, 1H),7.91 (d, J=8.3, 1H), 7.78 (d, J=8.3, 2H), 7.53 (d, J=4.9, 1H), 7.48 (d,J=3.0, 1H), 7.16 (app t, J=4.2, 1H).

Example 165 Preparation 12t

[1169] A mixture of bromide compound 12p (15.1 mg, 0.041 mmol),PdCl₂(PPh₃)₂ (4.6 mg, 0.007 mmol), 2-(tributylstannyl)-1-methylpyrrole(55 uL) and DMF (2 mL) was warmed to 100° C. for 3 h. The reactionmixture was cooled, filtered through a pad of celite with the aid of DMF(3×1 mL) and the filtrate was reduced by rotary evaporation. The residuewas triturated with ether (3×3 mL), and pentane (10×2 mL) and purifiedby chromatography (silica gel, 7% MeOH in CH₂Cl₂,) (3.8 mg, 25%) ¹H NMR(DMSO-d₆) δ13.26 (s, 1H), 11.43 (s, 1H), 10.24 (s, 1H), 9.03 (s, 1H),8.86 (d, 1H), 8.57 (d, 1H), 7.85 (d, 1H), 7.71 (dd, 1H), 6.91 (s, 1H),6.24 (dd, 1H), 6.14 (dd, 1H), 3.75 (s, 3H). MS m/e 367 (M+H)⁺.

Example 166 Preparation of 12u

[1170] A mixture of bromide compound 12p (21.5 mg, 0.059 mmol),PdCl₂(PPh₃)₂ (4.6 mg, 0.007 mmol), 4-(tributylstannyl)pyridine (100 uL)and DMF (2 mL) was warmed to 110° C. for 12 h. The reaction mixture wascooled, filtered through a pad of celite with the aid of DMF (3×1 mL)and the filtrate was reduced by rotary evaporation. The residue waspurified by chromatography (silica gel, 20% MeOH in CH₂Cl₂,) (1.8 mg,8%) ¹H NMR (DMSO-d₆) δ13.18 (s, 1H), 11.20 (s, 1H), 10.01 (s, 1H), 9.13(s, 1H), 8.65 (d, 1H), 8.46 (m, 2H), 8.33 (d, 1H), 7.83 (dd, 1H), 7.52(d 1H), 7.66 (m, 2H). MS m/e 365 (M+H)⁺.

Examples 166a-166d Preparation of 12v -12y

[1171] The following compounds 12v -12y were prepared in a mannersimilar to that described in Examples 147-166. TABLE 16 Example CompoundMass Spec (m/e) 166a 12v 402 (M + H) 166b 12w 386 (M + H) 166c 12x 427(M + H) 166d 12y 385 (M + H)

Example 166e Data for 12z

[1172] Compound 12z was prepared in a manner similar to that describedin Examples 147-166. ¹H-NMR (DMSO-d₆) δ13.4 (1H, s), 11.4 (1H, s), 10.2(1H, s), 9.1 (s, 1H), 8.86 (d, J=5.7 Hz 1H), 8.54, (d, J=5.7 Hz 1H),7.84 (s, 1H), 7.83-7.67 (m, 2H), 7.66 (d, J=15.8 1H), 7.0 (m, 1H), 6.70(d, J=15.8 Hz, 1H).

Example 166f Data for 12aa

[1173] Compound 12aa was prepared in a manner similar to that describedin Examples 147-166. ¹H-NMR (DMSO-d₆) δ13.5 (1H, s), 11.4 (1H, s), 10.2(1H, s), 9.1 (s, 1H), 8.86 (d, J=5.8 Hz 1H), 8.53, (d, J=5.8 Hz 1H),8.0-7.3 (m, 2H), 6.98 (m, 1H), 6.4 (d, J=16.6 Hz, 1H).

Example 166g Data for 12ab

[1174] Compound 12ab was prepared in a manner similar to that describedin Examples 147-166. ¹H-NMR (DMSO-d₆) δ13.3 (1H, s), 11.4 (1H, s), 10.2(1H, s), 9.1 (s, 1H), 8.85 (d, J=5.6 Hz 1H), 8.54, (d, J=5.1 Hz 1H),8.01 (d, J=10.1, 1H), 7.92 (d, J=16.1 Hz, 1H), 7.84-7.80 (m, 2H), 7.65(d, J=8.0, 1H), 7.34 (d, J=16.1 Hz, 1H), 7.28 (m, 1H).

Example 166h Data for 12ac

[1175] Compound 12ac was prepared in a manner similar to that describedin Examples 147-166. ¹H-NMR (DMSO-d₆) δ13.4 (1H, s), 11.4 (1H, s), 10.2(1H, s), 9.1 (s, 1H), 8.86 (d, J=5.8 Hz 1H), 8.61-8.50 (m, 2H), 8.01 (d,J 10.1, 1H), 7.85 (d, J=10.1, 1H), 7.80-7.25 (m, 5H).

Example 167 Preparation of 13a

[1176] To a mixture of imide 12a (28.5 mg, 0.10 mmol) in acetone (7 mL)was added MeI (250 uL). After stirring overnight, solvent was removed byrotary evaporation, and the residue was taken up in MeOH (7 mL) andtreated with NaBH₄ (15.2 mg, 0.4 mmol). After stirring overnight, thereaction was quenched with 1 N HCl (5 mL) and warmed to 50° C. Themixture was neutralized with aqueous NaHCO₃, extracted into EtOAc,washed successively with water and brine and dried over MgSO₄. Afterfiltration, solvent was removed by rotary evaporation, and the residuewas triturated with ether (3×3 mL) and dried under vacuum (14.9 mg,49%). ¹H NMR (DMSO-d₆) δ11.84 (s, 1H), 10.96 (s, 1H), 8.74 (d, J=7.8,1H), 7.54 (d, J=7.8, 1H), 7.49 (app. t, J=7.3, 1H), 7.25 (app t, J=7.3,1H), 3.95 (s, 2H), 3.25-3.00 (m, 2H), 2.85-2.65 (m, 2H), 2.41 (s, 3H).MS m/e 306 (M+H)⁺.

Example 168 Preparation of 13b

[1177] To a mixture of imide 12a (28.5 mg, 0.10 mmol) in acetone (7 mL)was added benzyl bromide (300 uL). After stirring overnight, solvent wasremoved by rotary evaporation, and the residue was triturated with ether(3×2 mL). This solid was taken up in MeOH (7 mL) and treated with NaBH₄(15.2 mg, 0.4 mmol). After stirring 3.5 h, the reaction was quenchedwith 1 N HCl (5 mL) and warmed to 50° C. The mixture was neutralizedwith aqueous NaHCO₃, extracted into EtOAc, washed successively withwater and brine and dried over MgSO₄. After filtration, solvent wasremoved by rotary evaporation, and the residue was purified bypreparative HPLC (45% MeCN/H₂O w/0.1% TFA, 6.5 mg, 17%). ¹H NMR(DMSO-d₆) δ11.87 (s, 1H), 10.93 (s, 1H), 8.74 (d, J=7.8, 1H), 7.54 (d,J=7.8, 1H), 7.60-7.20 (series of m, 8H), 4.05 (s, 2H), 3.74 (s, 2H),3.44-3.10 (m, 2H), 2.85-2.65 (m, 2H). MS m/e 382 (M+H)⁺.

Example 169 Preparation of 14

[1178] Benzofuran was treated with butyllithium in ether followed bycyclopentanone. The resulting alcohol was dehydrated withtoluenesulfonic acid in toluene to afford 2-cyclopenten-1-ylbenzofuran.Treatment with maleimide gave a cycloadduct which was aromatized bytreatment with tetrachloroquinone. ¹H NMR (DMSO-d₆) δ11.29 (s, 1H), 8.60(d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.52 (t, 1H), 3.23 (m, 4H), 2.30(quintet, 2H). MS m/e 276 (M−H)⁻.

Example 169a Preparation of 14a

[1179] 14a was prepared in a manner similar to that described in Example62j, starting with 6-methoxy-2-(1-hydroxycyclopentyl)indole to give thetitle compound. MS m/e 305 (m−1)⁺.

Example 169b Preparation of 14b

[1180] 14b was prepared in a manner similar to that described in Example62j, starting with 4-methoxy-2-(1-hydroxycyclopentyl)indole to give thetitle compound. MS m/e 305 (M−H).

Example 170 Preparation of 15

[1181] This compound was synthesized from benzothiophene according tothe same procedure described for compound 14. ¹H NMR (DMSO-d₆) δ11.36(s, 1H), 9.60 (d, 1H), 8.13 (d, 1H), 7.63 (m, 2H), 3.11 (m, 4H), 2.31(quintet, 2H). MS m/e 292 (M−H)⁻.

Examples 170a-170n Preparation of 15a-15n

[1182] Carbonate Intermediate: Compound 2ao (0.55 g, 1.9 mmol) and bis(4-nitrophenyl)carbonate (1.1.4 g, 3.76 mmol) were mixed in a sealedreaction tube and heated at 140° C. for 20 minutes. The solid wastriturated with ether and collected to 0.83 g MS m/e 456 (M−H).

[1183] Carbamates: A mixture of amine (0.09 mmol) and nitrophenylcarbonate intermediate (0.18 mmol) in dry THF (2 mL) under nitrogen washeated at 80° C. for 6 hours. The solvent was concentrated at reducedpressure and the residue triturated with ether and the productcollected. TABLE 17 Example Compound Mass Spec (m/e) 170a 14a 404 (M −H) 170b 14b 417 (M − H) 170c 14c 392 (M − H) 170d 14d 442 (M − H) 170e14e 459 (M − H) 170f 14f 425 (M − H) 170g 14g 439 (M − H) 170h 14h 453(M − H) 170i 14i 425 (M − H) 170j 14j 402 (M − H) 170k 14k 404 (M − H)170l 14l 419 (M − H) 170m 14m 447 (M − H) 170n 14n 439 (M − H)

What is claimed is:
 1. A compound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R² is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂,or HR³SO₂; J is: J³-(J²)_(n)-(¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or 2; with the provisos that when one of A and B isC(═O) and E and F, together with the atoms to which they are attached,form phenyl, then the other of A and B is other than C(═O), and when Aand B are C(═O), and Y and Z, together with the atoms to which they areattached, form unsubstituted indol-2,3-diyl, and R² is hydrogen, then Eand F, together with the atoms to which they are attached, form a groupother than unsubstituted imidazole or N-methylimidazole.
 2. The compoundof claim 1 wherein J³ is hydrogen, halo, hydroxy, thio, cyano, sulfonicacid, carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl,phosphonic acid, lower alkyl, lower alkyl ester of phosphonic acid, oraryl ester of phosphonic acid.
 3. The compound of claim 1 wherein E andF, together with the carbon atoms to which they are attached, form a C₅cycloalkyl group.
 4. A compound of formula IIaa:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; each of E and Fis, independently, lower alkyl; or E and F, together with the carbonatoms to which they are attached, form: a substituted or unsubstitutedC₄ to C₇ cycloalkyl group, wherein said substituted cycloalkyl group hasat least one substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; G is: O, S, SO, SO₂, NR²,NR³, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂; R¹ is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, lower arylsulfonyl, an amino acid, or a protected aminoacid; R^(2 n)is: hydrogen, lower alkyl, lower alkyl having at least onesubstituent J; formyl; acetyl, lower alkanoyl, lower alkanoyl having atleast one substituent J, lower alkylsulfonyl, arylsulfonyl, an aminoacid, or a protected amino acid; each of R³ and R⁴ is, independently,hydrogen, lower alkyl, aryl, lower alkyl having at least one substituentJ, or aryl having at least one substituent J; J is: J³-(J²)_(n)-(J¹)_(m)wherein each of n and m is, independently, 0 or 1; each of J¹ and J² is,independently, carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or 2; each of D¹ and D² is, independently, N(X¹),N(X²), C(R¹)(X¹), C(R¹)(X²), C(═O), S, or O; and each of X¹ and X² is,independently, hydrogen, halo, group J, lower alkyl, lower alkyl havingat least one substituent J, substituted or unsubstituted C₃ to C₇cycloalkyl wherein said substituted cycloalkyl group has at least onesubstituent J, substituted or unsubstituted C₂ to C₆ heterocycloalkylwherein said substituted heterocycloalkyl group has at least onesubstituent J, substituted or unsubstituted aryl wherein saidsubstituted aryl group has at least one substituent J, substituted orunsubstituted heteroaryl wherein said substituted heteroaryl group hasat least one substituent J; or X¹ and X², together with the atoms towhich they are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted aryl group whereinsaid substituted aryl group has at least one substituent J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one substituent J.
 5. The compound ofclaim 4 wherein J³ is hydrogen, halo, hydroxy, thio, cyano, sulfonicacid, carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl,phosphonic acid, lower alkyl, lower alkyl ester of phosphonic acid, oraryl ester of phosphonic acid.
 6. The compound of claim 4 wherein: eachof A and B is, independently, C(═O), CH₂, CH(OR³), or CH(SR³); E and F,together with the atoms to which they are attached, form: a substitutedor unsubstituted C₄ to C₇ cycloalkyl group wherein said substitutedcycloalkyl group has at least one substituent J; a substituted orunsubstituted C₃ to C₅ heterocycloalkyl group wherein said substitutedheterocycloalkyl group has at least one substituent J; or a substitutedor unsubstituted heterocycloalkyl group endocyclically comprising atleast one group G wherein said substituted heterocycloalkyl groupcomprising G has at least one substituent J; and G is: O, S, SO, SO₂,NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂.
 7. The compound of claim 4wherein: each of A and B is, independently, C(═O), CH₂, CH(OR³), orCH(SR³); and E and F, together with the atoms to which they areattached, form: a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or a substituted orunsubstituted heteroaryl group, wherein said substituted heteroarylgroup has at least one group J.
 8. A compound of formula IIbb:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; each of E and Fis, independently, lower alkyl; or E and F, together with the carbonatoms to which they are attached, form: a substituted or unsubstitutedC₄ to C₇ cycloalkyl group, wherein said substituted cycloalkyl group hasat least one substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; G is: O, S, SO, NR², NR,NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂; R¹ is: hydrogen, lower alkyl, loweralkyl having at least one substituent J, formyl, acetyl, lower alkanoyl,lower alkanoyl having at least one substituent J, lower alkylsulfonyl,lower arylsulfonyl, an amino acid, or a protected amino acid; R is:hydrogen, lower alkyl, lower alkyl having at least one substituent J;formyl; acetyl, lower alkanoyl, lower alkanoyl having at least onesubstituent J, lower alkylsulfonyl, arylsulfonyl, an amino acid, or aprotected amino acid; each of R³ and R⁴ is, independently, hydrogen,lower alkyl, aryl, lower alkyl having at least one substituent J, oraryl having at least one substituent J. J is: J³-(J²-(J¹)_(m) whereineach of n and m is, independently, 0 or 1; each of J¹ and J² is,independently, carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy,sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, loweralkylamido, lower dialkylamido, lower alkyloxycarbonylamino,aryloxycarbonylamino, amidino, guanidino, oxygen, sulphur, lower alkoxy,lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl,heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido,arylsulfonylamido, an amino acid, or a protected amino acid; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or 2; each of D¹ and D² is, independently, C(X¹),C(X²), or N; and each of X¹ and x² is, independently, hydrogen, halo,group J, lower alkyl, lower alkyl having at least one substituent J,substituted or unsubstituted C₃ to C₇ cycloalkyl wherein saidsubstituted cycloalkyl group has at least one substituent J, substitutedor unsubstituted C₂ to C₆ heterocycloalkyl wherein said substitutedheterocycloalkyl group has at least one substituent J, substituted orunsubstituted aryl wherein said substituted aryl group has at least onesubstituent J, substituted or unsubstituted heteroaryl wherein saidsubstituted heteroaryl group has at least one substituent J; or X¹ andX², together with the atoms to which they are attached, form: asubstituted or unsubstituted C₄ to C₇ cycloalkyl group wherein saidsubstituted cycloalkyl group has at least one substituent J; asubstituted or unsubstituted aryl group wherein said substituted arylgroup has at least one substituent J; or a substituted or unsubstitutedheteroaryl group wherein said substituted heteroaryl group has at leastone substituent J; with the provisos that when one of A and B is C(═O)and E and F, together with the atoms to which they are attached, formphenyl, then the other of A and B is other than C(═O), and when A and Bare C(═O), and D¹ and D² are C(X¹ ) or C(X²) in which X¹ and X²,together with the atoms to which they are attached, form unsubstitutedphenyl, and R² is hydrogen, then E and F, together with the atoms towhich they are attached, form a group other than unsubstituted imidazoleor N-methylimidazole.
 9. The compound of claim 8 wherein J³ is hydrogen,halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, lower alkyl,aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl, loweralkyl ester of phosphonic acid, or aryl ester of phosphonic acid. 10.The compound of claim 8 wherein: A is C(═O), CH₂, CH(OR³), or CH(SR³); Bis C(═O); and each E and F is, independently, CH₃; or E and F, togetherwith the carbon atoms to which they are attached, form a C₅ cycloalkylgroup.
 11. The compound of claim 8 wherein: A is C(═O); B is CH₂; and Eand F, together with the carbon atoms to which they are attached, form aC₅ cycloalkyl group.
 12. The compound of claim 8 wherein: each A and Bis, independently, C(═O), CH₂, CH(OR³), or CH(SR³); and E and F,together with the atoms to which they are attached, form: a substitutedor unsubstituted C₄ to C₇ cycloalkyl group wherein said substitutedcycloalkyl group has at least one substituent J; a substituted orunsubstituted C₃ to C₅ heterocycloalkyl group wherein said substitutedheterocycloalkyl group has at least one substituent J; or a substitutedor unsubstituted heterocycloalkyl group endocyclically comprising atleast one group G wherein said substituted heterocycloalkyl groupcomprising G has at least one substituent J; and G is: O, S, SO, SO₂,NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO².
 13. The compound of claim8 wherein: each A and B is, independently, C(═O), CH₂, CH(OR³), orCH(SR³); and E and F, together with the atoms to which they areattached, form: a substituted or unsubstituted aryl group, wherein saidsubstituted aryl group has at least one group J; or a substituted orunsubstituted heteroaryl group, wherein said substituted heteroarylgroup has at least one group J; with the provisos that when one of A andB is C(═O) and E and F, together with the atoms to which they areattached, form phenyl, then the other of A and B is other than C(═O),and when A and B are C(═O), D¹ and D² are C(X¹) or C(X²) in which X¹ andX², together with the atoms to which they are attached, formunsubstituted phenyl, and R² is hydrogen, then E and F, together withthe atoms to which they are attached, form a group other thanunsubstituted imidazole or N-methylimidazole.
 14. A compound of formulaIIIa:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; each of E and Fis, independently, lower alkyl; or E and F, together with the carbonatoms to which they are attached, form: a substituted or unsubstitutedC₄ to C₇ cycloalkyl group, wherein said substituted cycloalkyl group hasat least one substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising within the ringstructure at least one group G wherein said substituted heterocycloalkylgroup comprising G has at least one substituent J; a substituted orunsubstituted aryl group wherein said substituted aryl group has atleast one group J; or a substituted or unsubstituted heteroaryl groupwherein said substituted heteroaryl group has at least one group J; Gis: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂, or NR³SO₂; R¹ is:hydrogen, lower alkyl, lower alkyl having at least one substituent J,formyl, acetyl, lower alkanoyl, lower alkanoyl having at least onesubstituent J, lower alkylsulfonyl, lower arylsulfonyl, an amino acid,or a protected amino acid; R² is: hydrogen, lower alkyl, lower alkylhaving at least one substituent J; formyl; acetyl, lower alkanoyl, loweralkanoyl having at least one substituent J, lower alkylsulfonyl,arylsulfonyl, an amino acid, or a protected amino acid; each of R³ andR⁴ is, independently, hydrogen, lower alkyl, aryl, lower alkyl having atleast one substituent J, or aryl having at least one substituent J. Jis: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0 or1; each of J¹ and J² is, independently, carbonyl, lower alkylcarbonyl,arylcarbonyl, carbonyloxy, sulfonyl, amino, lower alkylamino, lowerdialkylamino, amido, lower alkylamido, lower dialkylamido, loweralkyloxycarbonylamino, aryloxycarbonylamino, amidino, guanidino, oxygen,sulphur, lower alkoxy, lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonylamido,alkylsulfonylamido, arylsulfonylamido, an amino acid, or a protectedamino acid; and J³ is: hydrogen, halo, hydroxy, thio, cyano, sulfonicacid, carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl,phosphonic acid, lower alkyl, lower alkyl ester of phosphonic acid, arylester of phosphonic acid, aminocarbonyloxy, heteroaryl, orheterocycloalkyl; and any two adjacent J groups can combine to form—X—(CH₂)_(p)—X—, wherein X is independently O or NH, and p is 1 or 2;and each of X¹ and x² is, independently, hydrogen, halo, group J, loweralkyl, lower alkyl having at least one substituent J, substituted orunsubstituted C₃ to C₇ cycloalkyl wherein said substituted cycloalkylgroup has at least one substituent J, substituted or unsubstituted C₂ toC₆ heterocycloalkyl wherein said substituted heterocycloalkyl group hasat least one substituent J, substituted or unsubstituted aryl whereinsaid substituted aryl group has at least one substituent J, substitutedor unsubstituted heteroaryl wherein said substituted heteroaryl grouphas at least one substituent J; or X¹ and X², together with the atoms towhich they are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted aryl group whereinsaid substituted aryl group has at least one substituent J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one substituent J; with the provisos thatwhen one of A and B is C(═O) and E and F, together with the atoms towhich they are attached, form phenyl, then the other of A and B is otherthan C(═O), and when A and B are C(═O), X¹ and X², together with theatoms to which they are attached, form unsubstituted phenyl, and R² ishydrogen, then E and F, together with the atoms to which they areattached, form a group other than unsubstituted imidazole orN-methylimidazole.
 15. The compound of claim 14 wherein J³ is hydrogen,halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, lower alkyl,aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl, loweralkyl ester of phosphonic acid, or aryl ester of phosphonic acid. 16.The compound of claim 14 wherein E and F, together with the atoms towhich they are attached, form a C₅ cycloalkyl group.
 17. The compound ofclaim 14 wherein X¹ and X² are a substituted or unsubstituted heteroarylgroup wherein said substituted heteroaryl group has at least onesubstituent J.
 18. The compound of claim 14 wherein A and B areindependently C(═O) or CH₂.
 19. The compound of claim 14 wherein E andF, when taken together with the carbon atoms to which they are attached,form a C₅ cycloalkyl group; X¹ and X² are a substituted or unsubstitutedheteroaryl group wherein said substituted heteroaryl group has at leastone substituent J; and A and B are independently C(═O) or CH₂.
 20. Thecompound of claim 19 wherein the substituted or unsubstituted heteroarylgroup is pyridyl or pyrimidyl; and A and B are C(═O).
 21. A compound offormula IVa:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; each of E and Fis, independently, lower alkyl; or E and F, together with the carbonatoms to which they are attached, form: a substituted or unsubstitutedC₄ to C₇ cycloalkyl group, wherein said substituted cycloalkyl group hasat least one substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising within at least onegroup G wherein said substituted heterocycloalkyl group comprising G hasat least one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; G is: O, S, SO, SO₂, NR²,NR³, NR²CO, NR²CONR³, NR²SO₂, or HR³SO₂; V is N(R¹), O, or S; R¹ is:hydrogen, lower alkyl, lower alkyl having at least one substituent J,formyl, acetyl, lower alkanoyl, lower alkanoyl having at least onesubstituent J, lower alkylsulfonyl, lower arylsulfonyl, an amino acid,or a protected amino acid; R² is: hydrogen, lower alkyl, lower alkylhaving at least one substituent J; formyl; acetyl, lower alkanoyl, loweralkanoyl having at least one substituent J, lower alkylsulfonyl,arylsulfonyl, an amino acid, or a protected amino acid; each of R³ andR⁴ is, independently, hydrogen, lower alkyl, aryl, lower alkyl having atleast one substituent J, or aryl having at least one substituent J. Jis: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is, independently, 0 or1; each of J¹ and J² is, independently, carbonyl, lower alkylcarbonyl,arylcarbonyl, carbonyloxy, sulfonyl, amino, lower alkylamino, lowerdialkylamino, amido, lower alkylamido, lower dialkylamido, loweralkyloxycarbonylamino, aryloxycarbonylamino, amidino, guanidino, oxygen,sulphur, lower alkoxy, lower aryloxy, aralkoxy, lower alkyl, C₃ to C₇cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonylamido,alkylsulfonylamido, arylsulfonylamido, an amino acid, or a protectedamino acid; and J³ is: hydrogen, halo, hydroxy, thio, cyano, sulfonicacid, carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl,phosphonic acid, lower alkyl, lower alkyl ester of phosphonic acid, arylester of phosphonic acid, aminocarbonyloxy, heteroaryl, orheterocycloalkyl; and any two adjacent J groups can combine to form—X—(CH₂)_(p)—X—, wherein X is independently O or NH, and p is 1 or 2;with the provisos that when one of A and B is C(═O) and E and F,together with the atoms to which they are attached, form phenyl, thenthe other of A and B is other than C(═O), and when A and B are C(═O), Vis NH, J and R² are hydrogen, then E and F, together with the atoms towhich they are attached, form a group other than unsubstituted imidazoleor N-methylimidazole.
 22. The compound of claim 21 wherein J³ ishydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, or aryl ester of phosphonic acid.23. The compound of claim 21 wherein V is N(R¹); groups E and F, whentaken together with the atoms to which they are attached, form a C₅cycloalkyl group; and A and B are independently C(═O) or CH₂.
 24. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 25. A pharmaceutical compositioncomprising a compound of claim 2 and a pharmaceutically acceptablecarrier.
 26. A method of inhibiting PARP, VEGFR2, or MLK3 activitycomprising contacting said PARP, VEGFR2, or MLK3 with a compound offormula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R² is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂,or HR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or
 2. 27. A method for treating or preventing aneurodegenerative disease comprising administering to a mammal atherapeutically effective amount of a compound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R² is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂,or NR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or
 2. 28. The method of claim 27 wherein saidneurodegenerative disease is Parkinson's, Huntington's, or Alzheimer'sdisease.
 29. A method for treating traumatic central nervous systeminjuries or preventing neuronal degradation associated with traumaticcentral nervous system injuries comprising administering to a mammal atherapeutically effective amount of a compound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or S₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R² is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO2 NR², NR³, NR²CO, NR²CONR³, NR²SO₂, orNR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or
 2. 30. A method for treating cerebral ischemia,cardiac ischemia, inflammation, endotoxic shock, or diabetes comprisingadministering to a mammal a pharmaceutically effective amount of acompound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂,CHR³, CHR³CHR⁴, CR³CR⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R² is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂,or NR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or
 2. 31. A method for suppressing the formation ofblood vessels in a mammal comprising administering to a mammal apharmaceutically effective amount of a compound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂,or NR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or
 2. 32. A method of treating cellularproliferative disorders comprising administering to a mammal apharmaceutically effective amount of a compound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R²is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR², NR³, NR²CO, NR²CONR³, NR²SO₂,or NR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or
 2. 33. The method of claim 32 wherein saidcellular proliferative disorders are related to solid tumors, diabeticretinopathy, intraocular neovascular syndromes, macular degeneration,rheumatoid arthritis, psoriasis, or endometriosis.
 34. A method oftreating cancer comprising administering to a mammal a pharmaceuticallyeffective amount of a compound of formula Ia:

wherein: each of A and B is, independently, C(═O), CH(OR³), CH(SR³),CH₂, CHR³, CHR³CHR⁴, CR³R⁴, C(═O)NR³, N═CR³, SO, or SO₂; Y and Z,together with the carbon atoms to which they are attached, form: asubstituted or unsubstituted aryl group, wherein said aryl group ismonocyclic or bicyclic and said substituted aryl group has at least onesubstituent J; a substituted or unsubstituted bicyclic heteroaryl group,wherein said substituted bicyclic heteroaryl group has at least onesubstituent J; or a C₃ to C₅ heteroaryl group; each of E and F is,independently, lower alkyl; or E and F, together with the atoms to whichthey are attached, form: a substituted or unsubstituted C₄ to C₇cycloalkyl group, wherein said substituted cycloalkyl group has at leastone substituent J; a substituted or unsubstituted C₃ to C₆heterocycloalkyl group wherein said substituted heterocycloalkyl grouphas at least one substituent J; a substituted or unsubstitutedheterocycloalkyl group endocyclically comprising at least one group Gwherein said substituted heterocycloalkyl group comprising G has atleast one substituent J; a substituted or unsubstituted aryl groupwherein said substituted aryl group has at least one group J; or asubstituted or unsubstituted heteroaryl group wherein said substitutedheteroaryl group has at least one group J; R² is: hydrogen, lower alkyl,lower alkyl having at least one substituent J, formyl, acetyl, loweralkanoyl, lower alkanoyl having at least one substituent J, loweralkylsulfonyl, arylsulfonyl, an amino acid, or a protected amino acid;each of R³ and R⁴ is, independently, hydrogen, lower alkyl, aryl, loweralkyl having at least one substituent J, or aryl having at least onesubstituent J. G is: O, S, SO, SO₂, NR²,NR³, NR²CO, NR²CONR³, NR²SO₂, orNR³SO₂; J is: J³-(J²)_(n)-(J¹)_(m) wherein each of n and m is,independently, 0 or 1; each of J¹ and J² is, independently, carbonyl,lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, loweralkylamino, lower dialkylamino, amido, lower alkylamido, lowerdialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino,amidino, guanidino, oxygen, sulphur, lower alkoxy, lower aryloxy,aralkoxy, lower alkyl, C₃ to C₇ cycloalkyl, heterocycloalkyl, aryl,heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, anamino acid, a protected amino acid, aminocarbonyloxy,arylaminocarbonyloxy, or heteroarylaminocarbonyloxy; and J³ is:hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, carboxyl, loweralkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl,lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid,aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and any two adjacentJ groups can combine to form —X—(CH₂)_(p)—X—, wherein X is independentlyO or NH, and p is 1 or 2.